INTRODUCTION
Currently, there are more than 20 million new cancer diagnoses globally, with 10 million cancer-related deaths [1,2]. Surgery, radiotherapy, chemotherapy, and targeted therapy (TT) are traditional methods that continue to be the standards of care for all cancer types. Patients with metastatic forms of cancer face significant challenges when relying solely on conventional methods [3]. Immune checkpoint inhibitors (ICIs) are therapeutic agents that block the interaction of cytotoxic T-cells with proteins, including programmed cell death 1 (PD-1), programmed death-ligand 1 (PD-L1), and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), thus enhancing T-cellmediated immune responses against neoplastic cells [4]. Immunotherapy has changed the treatment landscape for nonsmall cell lung cancer (NSCLC) and gastric cancer (GC). ICIs have emerged as the cornerstone for managing these two cancer types by enhancing their responses, increasing longterm survival, and exhibiting better toxicity profiles than chemotherapy.
Unlike other forms of personalized cancer treatment, such as adoptive cell transfer that involves the reinfusion of ex vivo expanded autologous T-cells [5], ICI works by blocking proteins used by cancer cells, unleashing the immune system’s ability to recognize and attack cancer effectively. Widely studied of recent advancement and most common ICIs include monoclonal antibodies targeting PD-1 (pembrolizumab, nivolumab, cemiplimab), CTLA-4 (ipilimumab), and PD-L1 (atezolizumab, avelumab, durvalumab). Among these, ICIs have demonstrated substantial efficacy both in NSCLC and GC, making them an essential component of modern oncology treatment strategies [6]. These advancements in cancer therapy underscore the significant role of ICIs in treating cancer types and leveraging the body’s immune system to specifically target and combat tumor cells, thereby improving patient survival rates [4,7].
EFFICACY OF IMMUNE CHECKPOINT INHIBITORS IN KOREAN STUDIES
According to GLOBOCAN, there are 11.4% of the 19.3 million lung cancer cases incidence and mortality in 2020 worldwide with 1.8 million deaths. NSCLC is the most common type of lung cancer and accounts for 80% to 85% of all cases [8]. In South Korea, NSCLC ranks as the most prevalent cancer, accounting for 13.2% of all cases in both sexes [9]. NSCLC is characterized by the abnormal growth of cells that, if left untreated, can spread to other parts of the body [10]. Surgery, chemotherapy, radiation therapy, or a combination of these modalities are among the curative therapies for stage I and stage II lung cancer or NSCLC. However, treatment depends on the patient’s functional status, comorbidities, tumor stage, and molecular profile of the disease. Table 1 summarizes the efficacy of ICIs, including nivolumab, pembrolizumab, atezolizumab, and durvalumab, in improving the survival outcomes of patients with NSCLC [11-17].
Table 1 summarizes of key applications, efficacy metrics, and clinical findings of ICIs in the treatment of NSCLC and GC, as observed in studies in Korea and Japan. It highlights the utility of ICIs such as nivolumab, pembrolizumab, atezolizumab, and durvalumab, demonstrating their efficacy in improving overall survival (OS) and progression-free survival (PFS) compared to conventional therapies. ICI in NSCLC show higher objective response rate (ORR) and disease control rate (DCR), indicating improved therapeutic efficacy and disease management. Nivolumab and pembrolizumab in GC yielded remarkable outcome, particularly in biomarker-positive populations.
Non-small cell lung cancer
Progress in ICIs in South Korea, such as pembrolizumab and nivolumab, is changing the treatment of metastatic NSCLC. Ji et al. [11] studied patients with stage IIIB or stage IV NSCL who underwent palliative chemotherapy and explored how the use of ICIs after platinum-based cytotoxic chemotherapy (CC) affected their outcomes. The study revealed that patients who received drugs such as nivolumab and pembrolizumab as second-line treatment had shorter median OS (11.7± 12.0 months for nivolumab and 12.9± 12.3 months, for pembrolizumab) compared to TT but still outperformed CC. Patients in the TT group had a progression survival (9.4± 12.3 months) and those in the CC group had a shorter survival period (6.7 ± 9.2 months). The median PFS for nivolumab and pembrolizumab was 7.7± 10.1 and 9.0± 10.9 months, respectively, shorter than that for TT but was longer than that for CC among the ICI group. Kaplan–Meier analysis revealed that the ICI group had a longer survival time than the non-ICI group. In another study, ICI showed advantages in neoadjuvant treatment, as evidenced by OS data from randomized controlled trials (RCTs). IMpower010 (atezolizumab) and PEARLS/KEYNOTE-091 (pembrolizumab) are two notable RCTs that have shown significant improvements in the primary endpoint of disease-free survival. The IMpower010 trial achieved a hazard ratio (HR) of 0.81 whereas the PEARLS/KEYNOTE-091 study reported an HR of 0.76, both with a 95% confidence interval (CI), underscoring the efficacy of ICIs in improving patient outcomes. Advanced ICI treatments can lower the risk of death and slow disease progression more effectively than conventional chemotherapy [18].
A real-world study conducted by Ham et al. [12] at the VHS Medical Center in Korea evaluated the efficacy of ICIs in 180 patients with stage IV NSCLC with a median age of 76 years, focusing on nivolumab, pembrolizumab, and atezolizumab. The patients were grouped according to treatment: 27.7% of the patients received pembrolizumab, 33.9% received nivolumab, and 38.9% received atezolizumab. The study demonstrated higher ORR for pembrolizumab and nivolumab than for atezolizumab, with an ORR of 22.4% for pembrolizumab, 8.2% for nivolumab, and 4.3% for atezolizumab. Furthermore, the DCR improved with pembrolizumab (59.2%) and nivolumab (55.7%) compared with atezolizumab (30.0%). The OS outcomes among the three groups were similar; pembrolizumab showed OS of 12.6 months, nivolumab 8.4 months, and atezolizumab 7.7 months. PFS showed no significant differences in survival outcomes. Ham et al. [12] highlighted that pembrolizumab and nivolumab were associated with higher ORR and DCR than atezolizumab, with PD-L1 expression playing a potential, albeit non-significant, role in survival outcomes.
A recent retrospective study demonstrated the contribution of consolidative durvalumab to improving outcomes in patients with unresectable locally advanced non-small cell lung cancer (LA-NSCLC) following concurrent chemoradiotherapy (CCRT) at the Asan Medical Center. Jang et al. [13] evaluated the real-world effectiveness of durvalumab in 171 patients, of whom 89 received durvalumab after CCRT and 82 underwent CCRT alone. Median PFS was significantly higher in the durvalumab group (20.9 months) than in the CCRT-only group (13.7 months). Patients treated with durvalumab showed a markedly improved rate of 57.3% compared with 38.8% in those receiving only CCRT in the 3-year freedom from locoregional failure (FFLRF) rate. These results were corroborated by the higher incidence of in-field recurrence (12.4%) in the durvalumab group than in the CCRT alone group (26.8%). However, 35.4 months was reported for the CCRT-only group, indicating a substantial survival advantage compared with durvalumab. In addition, patients with PD-L1-positive tumors demonstrated better outcomes across all survival metrics, such as FFLRF, distant metastasis-free survival, PFS, and OS, highlighting the importance of biomarkers in stratifying pa-tients for ICI therapies. Real-world data showed greater applicability than durvalumab in clinical trials, improving locoregional control, PFS, and OS, underscoring the pivotal role of durvalumab in advancing the treatment paradigm for unresectable LA-NSCLC. These findings support the inclusion of durvalumab as a standard of care after CCRT in patients with PD-L1-positive tumors for personalized and effective cancer treatment.
Gastric cancer
GC is the fifth most commonly diagnosed cancer [19], continues to be a significant global health burden, and is the fourth leading cause of cancer-related deaths [20]. Approximately 60% of cases occur in Eastern Asian countries, with South Korea and Japan ranking 3rd accounting for 12.3% and 12.6% of all cases in both sexes [9,21,22]. The prognosis of advanced GC, with a 5-year survival rate of less than 40%, remains challenging despite advances in surgical techniques and therapies.
In a multicenter retrospective study conducted by Lim et al. [14] in 17 tertiary referral centers in Korea, 363 patients with histologically or cytologically confirmed gastric or gastroesophageal junction adenocarcinomas underwent third-line treatment. In this study, 129 patients were treated with ICIs (nivolumab and pembrolizumab) and 234 were treated with irinotecan-based chemotherapy (irinotecan monotherapy in combination with 5-fluorouracil, leucovorin, and irinotecan [FOLFIRI]). The ICI group had a slightly shorter (5.5 months) OS than irinotecan-based chemotherapy group (6.0 months). Meanwhile the PFS of ICI group showed a median of 2.3 months compared to 2.9 months in the irinotecan-based chemotherapy group. A multivariable analysis revealed factors such as weight loss, peritoneal metastasis, low serum sodium or albumin levels, and a shorter duration of second-line treatment (paclitaxel plus ramucirumab therapy) were significantly associated with poorer OS. Furthermore, ICI significantly demonstrated a longer OS than irinotecan-based chemotherapy in patients without peritoneal metastasis, while ICI resulted in shorter OS among patients without PD-L1 expression. Moreover, in a subset patient with microsatellite instability-high (MSI-H)/deficient mismatch repair (d-MMR) or Epstein– Barr virus (EBV)-positive tumors, ICI treatment is associated with prolonged PFS compared to irinotecan-based chemotherapy (12.7 months vs 2.8 months). Certain biomarker-defined subgroups may benefit more from immunotherapy than from conventional chemotherapy. Additionally, PDL1 (62% vs. 39%) and MSI-H/MMR-deficient tumors (9% vs. 3%) were more common in the ICI group than in the chemotherapy group, indicating that ICIs are beneficial in patients with favorable biomarker profiles. The biomarker status of human epidermal growth factor receptor 2 (HER2)- and EBV-positive tumors is important in selecting patients for ICI therapy, emphasizing the survival advantage, with HER2-positive tumors common in the ICI group (14% vs. 11%) and EBV-positive tumors more prevalent in the chemotherapy group (6% vs. 2%) [14] .
A separate retrospective study by Park et al. [17] in patients receiving first-line treatment with histologically confirmed metastatic, recurrent, or locally advanced unresectable gastric or gastroesophageal junction adenocarcinoma with d-MMR tumors at the Asan Medical Center, Seoul, Korea. Compared to chemotherapy alone, nivolumab chemotherapy significantly improved PFS (not reached vs. 5.2 months and showed a trend toward longer OS (not reached vs. 17.9 months). Patients with a lower neutrophil-to-lymphocyte ratio (NLR < 3.80) were more pronounced in survival benefit, while survival outcomes were poor in patient with those nivolumab plus chemotherapy with higher NLR (≥ 3.80). Additionally, PD-L1 combined positive score did not significantly impact survival outcomes, highlighting nivolumab chemotherapy as an effective first-line treatment for d-MMR GC. However, its efficacy may be limited in patients with high systemic inflammation (high NLR).
EFFICACY OF IMMUNE CHECKPOINT INHIBITORS IN JAPANESE STUDIES
Non-small cell lung cancer
In Japan, a retrospective multicenter study examined patients who started anti-PD-1 inhibitor monotherapy, including elderly and younger patients with NSCLC treated with nivolumab or pembrolizumab between December 2015 and December 2017. Among the 676 patients, 137 were elderly, with a median age of 78 years, a smoking history, an Eastern Cooperative Oncology Group-Performance status (ECOG PS) of 0 or 1, and no known driver mutations (epidermal growth factor receptor [EGFR], anaplastic lymphoma kinase [ALK] translocation, ROS1, and BRAF), while their younger counterparts were aged 66 years. The PFS in the elderly group was 4.8 months, which was similar to that of the younger group (3.3 months). The OS was comparable between the elderly (12.3 months) and younger (12.7 months) groups, with 95% CI. This confirms that ICI therapy is effective in elderly patients with NSCLC, and that age is not a prognostic factor for response to therapy [23]. This is supported by a study conducted by Nosaki et al. [24] in a clinical trial using a pooled data analysis of KEYNOTE-010, KEYNOTE-024, and KEYNOTE-042, which demonstrated the safety and effectiveness of pembrolizumab monotherapy among patients aged 75 years and older, consistent with those observed in the general population.
A recent study conducted by Asano et al. [25] at the Kanazawa University Hospital in Japan examined 29 patients with NSCLC. The ICIs pembrolizumab, nivolumab, and atezolizumab demonstrated notable effects in patients with advanced NSCLC, including those with bone metastases. A total of 21 cases showed a control rate of 72.4% when treated with ICIs, of whom 16 patients were administered pembrolizumab and showed a substantial therapeutic impact on both primary lung lesions and bone metastases. Partial response (PR) was achieved in 18.8% of lung lesions, with complete response in 12.5% and PR in 31.2% of bone metastases, according to the RECIST 1.1 and MD Anderson Cancer Center (MDA) criteria. Meanwhile, nivolumab and atezolizumab exhibited efficacy in disease management, showing stable disease or progressive disease in both lung lesions and bone metastases. The combination of pembrolizumab with bone-modifying agents (BMAs), including denosumab and zoledronic acid, enhances its efficacy, particularly for bone metastases. This therapy is promising for NSCLC, even in cases of impending lower extremity fractures. Therefore, these findings underscore that ICIs combined with BMA could offer comprehensive NSCLC treatment, which represents an approach that warrants further study in more diverse NSCLC patients.
Gastric cancer
Kadono et al. [15] conducted a single-institution retrospective study at the National Cancer Center Hospital in Japan, analyzing 1,918 patients with GC between 2010 and 2020. In the context of post-2017 treatments for advanced GC, Japan approved the most commonly used ICIs for HER2-negative and PD-L1-positive patients, including nivolumab and pembrolizumab. Median OS was significantly longer in patient treated during post-2017 with ICIs compared to pre-2017 (16.9 months vs. 13.9 months). Patients treated during post-2017 also had a higher percentage of transitioning to third-line treatment than those treated during pre-2017 (56.3% vs. 43.8%). In addition, after progression, median OS (4.3 months vs. 3.2 months) after second-line therapy was longer in the post-2017 group. This underscores the role of ICIs in advancements in GC treatment.
A multi-institutional study was conducted by Matsumoto et al. [16] in Japan from August 2018 to January 2021 to investigate the effect of trastuzumab deruxtecan (T-DXd) in patients with HER2-positive advanced gastric cancer (AGC). Patients were treated with 6.4 mg/kg T-DXd via infusion every 3 weeks, lasting until disease progression.
The ORR was 41% and the DCR was 76%, with median PFS of 3.9 months and OS of 6.1 months. Similarly, patients who received prior ICIs such as nivolumab and pembrolizumab demonstrated longer PFS of 6.5 months and OS of 6.2 months compared to those without prior ICI therapy (PFS, 2.9; OS, 3.7). Meanwhile, T-DXd demonstrated a response rate of 41%, median PFS of 3.9 months, and median OS of 6.5 months suggesting that it is an effective treatment for HER2-positive AGC patients. However, for T-DXd efficacy, pre-administration of ICIs and sufficient Tmab-free intervals were considered predictive factors.
Adverse effects of ICIs
Utilization of ICIs in cancer has significantly expanded across various cancer types and stages in the field of cancer treatment, offering new hope to patients who have been previously diagnosed with difficult-to-treat malignancies. The number of patients eligible for ICI therapy increased in 2018 from 1.54% in 2011 to 43.63% after its initial approval in March 2011 [26]. Additionally, there was an increase in the response rate, as measured by the reduction or shrinkage of cancer, following treatment from 0.14% to 12.46% over the same period [27]. These drugs, including pembrolizumab, nivolumab, atezolizumab, and durvalumab, release the immune system to attack cancer cells more effectively [28]. Frequent immune-related adverse events (irAEs), as observed with PD-1, PD-L1, and CTLA-4 inhibitors primarily affect the gastrointestinal, endocrine, and dermatologic systems while, severe and potentially fatal irAEs include neurotoxicity, cardiotoxicity, and pulmonary toxicity [29]. The most commonly observed irAEs include dermatitis/rash, thyroiditis, pneumonitis, hepatitis, and colitis [30] as summarized in Table 2, which highlights the spectrum of irAEs observed with these therapies and their severity levels [29,31-40].
While most irAEs associated with ICIs are manageable, rare but severe irAEs can occur, affecting multiple organ systems and leading to life-threatening complications. ICIs are associated with the onset of new autoimmune conditions such as ts diabetes (T1DM) in individuals with no prior history of the disease. For instance, the pathogenesis of ICI-induced T1DM (ICIT1DM) is linked to the disruption of immune tolerance, resulting in the autoimmune destruction of pancreatic β-cells. The inhibition of ICI, such as PD-1 (pembrolizumab, nivolumab, and cemiplimab), PD-L1 (atezolizumab, avelumab, and durvalumab), and CTLA-4 (ipilimumab and tremelimumab), which prevent autoimmunity, is primarily mediated by T-cell activation. However, it can also trigger autoimmune side effects that can precipitate rapid β-cell destruction, culminating in insulin deficiency and the onset of T1DM. Ketoacidosis (diabetic ketoacidosis) is the initial manifestation of ICI-T1DM in many patients with diabetes [41]. Anti-PD-1 and anti-PD-L1 therapies are more frequently associated with ICI-T1DM than anti-CTLA-4 therapies. Furthermore, ICI-T1DM may exhibit distinct features, such as a more rapid progression to insulin dependence and a lower prevalence of diabetes-associated autoantibodies than T1DM [42,43].
Gastrointestinal irAEs resulting from ICI therapy have also been observed compared to those associated with traditional chemotherapy [44]. A comprehensive meta-analysis conducted by Yasuda et al. [36] highlighted colitis as a notable gastrointestinal complication arising from ICI therapy following prolonged nivolumab treatment in patients with NSCLC. A 62-year-old male patient developed colitis after long-term nivolumab therapy, characterized by non-bloody watery diarrhea and abdominal pain. The presence of colitis was confirmed using diagnostic tests, including colonoscopy and histopathological examination. Discontinuation of nivolumab and initiation of corticosteroid therapy improved the symptoms.
Ocular adverse events (OAEs) are rare but serious complications associated with the risk of non-infectious uveitis during ICI treatment. These events can manifest in various forms, including uveitis, which is an inflammation of the uvea (the middle layer of the eye), and retinal detachment, a condition in which the retina separates from the underlying supportive tissue. In a retrospective cohort study by Chang et al. [33], patients receiving conventional chemotherapy was 0.20%, nearly double the 0.11% incidence on any-grade uveitis in ICI treatment. Severe uveitis cases were more frequent in the ICI group, with 16.7% mild cases of recurrence and 41.7% severe cases of ICI rechallenge. Furthermore, patients with skin melanoma or lung cancer undergoing treatment with ICI had 0.35% cumulative incidence rate of uveitis [34]. A similar study conducted by Kim et al. [32] involving 40 patients undergoing ICI therapy (e.g., atezolizumab, pembrolizumab, nivolumab, and ipilimumab/nivolumab) demonstrated a higher incidence rate of OAE (anterior uveitis, posterior uveitis, panuveitis, and optic neuritis). Five patients developed intraocular inflammation, one developed bilateral anterior uveitis after nivolumab and ipilimumab combination treatment, and four developed panuveitis or neuroretinitis after pembrolizumab treatment. In addition, patients with a history of autoimmune diseases were more susceptible to developing OAEs [45].
A separate retrospective analysis conducted by Hyun et al. [31] at the National Cancer Center (NCC) in Korea examined 1,503 patients treated with ICIs, including PD1 (nivolumab and pembrolizumab), PD-L1 (atezolizumab), and CTLA-4 (ipilimumab), who experienced irAEs (grade 3 or higher). Nine patients with a median age of 59 years (0.6%) experienced severe irAEs (five and four cases in the pembrolizumab and atezolizumab groups, respectively), which are relatively rare but significantly important as they affect ICI therapy. Neuromuscular irAEs manifest as Guillain-Barré syndrome [46], myopathy, and myasthenia gravis (MG) [40], which are serious autoimmune conditions that affect the nervous system. However, most patients (80%) who were initially administered ICIs within 3 months of ICI therapy experienced neuromuscular irAEs [31].
Another retrospective study conducted by Hashimoto et al. [39] at Kyushu University Hospital’s Department of Dermatology examined 51 patients who developed cutaneous irAEs during treatment with nivolumab, pembrolizumab, ipilimumab, atezolizumab, avelumab, and durvalumab. In these patients, cutaneous irAEs were associated with nivolumab (24/51 patients) and pembrolizumab (13/51 patients). ICI combination therapy with nivolumab and ipilimumab (six cases), atezolizumab (four cases), avelumab (two cases), or ipilimumab (two cases) was administered. The most common cutaneous irAEs were maculopapular rash, erythema multiforme, lichenoid reactions, psoriasiform reactions, and autoimmune diseases such as bullous pemphigoid [47] and scleroderma-like reactions [48].
A retrospective case report conducted by Satoh et al. [37] analyzed 95 cases of Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) induced by ICIs and found that 58.9% of the severe cutaneous adverse events were caused by PD-1 inhibitors. A total of 11.6% of the cases were due to combination therapy with PD-1 and CTLA-4 inhibitors and 6.3% were associated with PD-L1 inhibitors. In total, 35.8% of affected patients were undergoing treatment for lung cancer. For the SJS/TEN cases, 51.7% occurred within the first few weeks of ICI therapy initiation.
Other common irAEs include gastrointestinal toxicity such as diarrhea and abdominal pain, which may worsen the life-threatening conditions of intestinal perforation. Endocrine toxicities include hypothyroidism, hyperthyroidism, and thyroiditis [31]. Hepatic manifestations with increased liver enzyme levels can result in liver failure. The renal side effects include acute interstitial nephritis (AIN) and acute kidney injury (AKI) [38]. Pulmonary toxicities include pneumonitis. Cardiotoxicity manifests as myocarditis and arrhythmias, leading to heart failure. Dermatological adverse events include rashes, pruritus, and severe skin reactions, including SJS and TEN [37]. Neurological toxicities include MG [35,40], encephalitis, and peripheral neuropathy. Other blood related side effects include anemia, thrombocytopenia, and leukopenia; ophthalmic side effects comprise uveitis and conjunctivitis [33,49]. IrAEs affect multiple organs and can be fatal if not identified and managed early [18].
CONCLUSION
Current evidence from Korean and Japanese studies demonstrates a paradigm shift toward the use of ICI treatment in NSCLC and GC. These therapies have demonstrated substantial improvements in disease outcomes, particularly in biomarker-positive patients, and represent a major step toward advancing the field of precision oncology. Besides improving survival rates, ICIs provide robust disease control for disease management in cancer patient with limited options and alternatives to conventional therapies. However ICIs are probably not cost-effective as it varies depending on the drug and dosage, with high prices primarily attributed to expensive research and complex manufacturing processes.
However, their clinical use is associated with adverse effects. The issue of irAEs remains a significant concern among clinicians; hence, there is a need for close monitoring and efficient control systems to ensure safety while achieving efficacy. The results from various publications emphasize the need for research on combination therapy, including ICI treatment with BMA or chemoradiation, for the management of certain diseases, including metastatic conditions. Furthermore, leveraging biomarkers, such as PD-L1 expression and MSI-H/MMR-deficient status, for target ICI patient selection is critical for optimizing outcomes.
Looking forward, emerging ICIs and combination therapies like dual checkpoint blockade strategies and combination therapy (targeted and adiation therapy) are currently investigated to enhance treatment efficacy and overcome resistance mechanisms. Lymphocyte-activation gene 3 (LAG-3), T-cell immunoreceptor with Ig and ITIM domains (TIGIT) has been extensively evaluated in clinical trials in patients with different types of cancer in recent years expanding the scope of immunotherapy. To advance ICI treatments further, future research should focus on refining patient selection criteria and identifying predictive biomarkers enhancing treatment efficacy and minimize toxicities. Clinical guidelines such as standardized protocols for irAEs management, and health policies should explore strategies to improve affordability and accessibility of ICIs treatment. A real-world study evaluates longterm survival benefits and cost-effectiveness. Expanding multi-institutional collaborations and incorporating artificial intelligence-driven predictive modeling could further personalize ICI therapy. Although ICIs are redefining cancer treatment in East Asia, thorough and continuous investigations are required to optimize treatment strategies, control irAEs, and expand their benefits to a greater number of patients with cancer. This will ensure that ICIs reach their full potential as one of the main pillars of current cancer therapies.
PDF Links
PubReader
ePub Link
XML Download
Full text via DOI
Download Citation
Print
