Lung Cancer Treatment in the Era of Immunotherapy

Lung Cancer Treatment in the Era of Immunotherapy

Lung cancer remains one of the most common and deadly malignant tumors, posing a significant threat to human health. Despite advancements in chemotherapy, radiotherapy, and targeted therapy, the prognosis for lung cancer patients remains poor. However, the advent of immunotherapy, particularly immune checkpoint inhibitors (ICIs), has revolutionized the treatment landscape, offering new hope for patients.

Immune checkpoint inhibitors are monoclonal antibodies designed to block immune checkpoints, which are proteins that inhibit the immune system’s ability to attack cancer cells. By blocking these checkpoints, ICIs restore the body’s anti-tumor immune response, enhancing the clearance of tumor cells. The most commonly used ICIs include programmed cell death (PD)-1 inhibitors (such as nivolumab and pembrolizumab), PD-ligand 1 (PD-L1) inhibitors (such as atezolizumab and durvalumab), and cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) inhibitors (such as ipilimumab and tremelimumab).

The application of ICIs has evolved from second-line treatment to neoadjuvant therapy. Early studies, such as CheckMate 017, CheckMate 057, KEYNOTE 010, and OAK, demonstrated that ICIs significantly improved objective response rates (ORR), progression-free survival (PFS), and overall survival (OS) compared to chemotherapy. Updated data from the CheckMate 017/CheckMate 057 studies revealed a notable improvement in the 5-year survival rate for patients treated with ICIs, indicating the potential for long-term survival with immunotherapy.

The National Comprehensive Cancer Network (NCCN) guidelines recommend nivolumab, pembrolizumab, and atezolizumab as second-line treatments for non-small-cell lung cancer (NSCLC). Additionally, immunotherapy has shown efficacy in second-line treatment for small cell lung cancer (SCLC). For example, the CheckMate 032 study reported prolonged survival in patients with recurrent SCLC treated with nivolumab, either alone or in combination with ipilimumab. Similarly, the KEYNOTE 028 and KEYNOTE 158 studies demonstrated the benefits of pembrolizumab in advanced SCLC patients.

ICIs have also proven effective as first-line treatments. The KEYNOTE 024 study showed that first-line pembrolizumab treatment in patients with high PD-L1 expression (PD-L1 ≥50%) resulted in better ORR and PFS compared to standard platinum-based chemotherapy. The 3-year follow-up data from KEYNOTE 024 indicated a median OS of 26.3 months for the immunotherapy group, with greater survival benefits for patients with high PD-L1 expression. The KEYNOTE 042 study further expanded the applicability of first-line immunotherapy, demonstrating that pembrolizumab prolonged OS in NSCLC patients with PD-L1 expression ≥1%, with even greater benefits for those with PD-L1 expression ≥50%.

In addition to advanced lung cancer, ICIs have been explored in neoadjuvant therapy for early-stage NSCLC. The CheckMate 159 study administered nivolumab to patients with untreated stage I–IIIa resectable NSCLC for two cycles before surgery, achieving a major pathologic response (MPR) rate of 43%. The treatment was well-tolerated and did not delay surgery. Updated data from CheckMate 159 presented at the 2019 American Society of Clinical Oncology meeting showed a median follow-up time of 34.6 months, with the median recurrent-free survival not yet reached. Other studies, including LCMC3, NADIM, MAC, and NEOSTAR, have also confirmed the efficacy of immunotherapy in neoadjuvant treatment for early-stage NSCLC.

The combination of immunotherapy with other treatment modalities has shown promising results. Synergistic effects have been observed when ICIs are combined with chemotherapy, radiotherapy, anti-angiogenic targeted therapy, and dual combination immunotherapy. Studies such as KEYNOTE 407, KEYNOTE 189, and IMpower 132 demonstrated that combining immunotherapy with chemotherapy is an effective first-line treatment strategy for advanced NSCLC without driver gene mutations. Similarly, the IMpower 133, KEYNOTE 604, and CASPIAN studies showed that combining chemotherapy with immunotherapy significantly prolonged survival in SCLC patients.

Radiotherapy can enhance the immune response by promoting the release of tumor antigens. The KEYNOTE 001 study found that patients who underwent radiotherapy before immunotherapy had extended PFS and OS by 2.3 and 5.4 months, respectively, compared to those receiving pembrolizumab monotherapy. Anti-angiogenic drugs, such as bevacizumab, can inhibit tumor growth and enhance the immune response. The IMpower 150 study showed that atezolizumab combined with bevacizumab and chemotherapy prolonged OS in lung cancer patients, leading to its approval for first-line treatment of driver gene-negative non-squamous NSCLC.

Dual combination immunotherapy, such as combining CTLA-4 and PD-1/PD-L1 inhibitors, can enhance anti-tumor effects through complementary mechanisms. The CheckMate 012 and CheckMate 227 studies demonstrated clinical benefits of nivolumab combined with ipilimumab in first-line treatment for advanced NSCLC patients. As lung cancer treatment methods continue to evolve, combined immunotherapy is increasingly recognized and will be a focus of future research.

The development of ICIs has also advanced precision immunotherapy for lung cancer. Identifying biomarkers that predict immunotherapy response is crucial for improving treatment efficacy. PD-L1 expression is a well-established biomarker, with the NCCN guidelines recommending its detection in initially-treated advanced NSCLC patients. However, PD-L1 testing has limitations, including variability in reagents, subjective interpretation of results, and the inability to dynamically monitor PD-L1 levels.

Tumor mutation burden (TMB) has emerged as another potential biomarker, with studies such as CheckMate, POPLAR, and OAK suggesting a correlation between TMB and immunotherapy efficacy. The 2019 NCCN guidelines recommend using TMB to identify beneficiaries of dual-agent immunotherapy with nivolumab plus ipilimumab and single-agent immunotherapy with nivolumab. However, TMB’s high cost, long measurement period, and lack of unified standards have limited its widespread use.

Other potential biomarkers include mismatch repair genes, microsatellite instability, tumor microenvironment, body immune status, and intestinal flora composition. The discovery of these predictive indicators promotes the development of individualized precision immunotherapy for lung cancer.

In China, both international and domestic immunotherapy drugs are being developed and approved. Toripalimab was the first domestic PD-1 inhibitor approved in China, followed by sintilimab, camrelizumab, and tislelizumab. Clinical trials on domestic ICIs for lung cancer therapy have shown promising results. For example, a phase II study on camrelizumab as a second-line treatment for advanced/metastatic NSCLC reported an ORR of 18.5%, comparable to imported PD-1 inhibitors. Phase III studies on camrelizumab and tislelizumab in combination with chemotherapy demonstrated significant improvements in PFS and OS compared to chemotherapy alone.

Despite the advancements, immunotherapy presents challenges, including immune-related adverse events (irAEs). ICIs can activate non-specific immune reactions, leading to irAEs such as immune-related pneumonitis, interstitial nephritis, and myocarditis. Most irAEs are mild to moderate and manageable with temporary drug withdrawal or glucocorticoid therapy. However, serious irAEs, such as checkpoint inhibitor pneumonitis (CIP), can be life-threatening. The Chinese Thoracic Society has developed guidelines to help clinicians diagnose and treat CIP effectively.

Drug resistance is another challenge in immunotherapy, with patterns including primary, adaptive, and acquired resistance. Mechanisms of resistance involve tumor cells, immune cells, and the tumor microenvironment. Addressing immunotherapy resistance, optimizing combination regimens, and identifying optimal biomarkers are critical areas for future research.

In conclusion, immunotherapy has transformed lung cancer treatment, shifting from second-line to first-line therapy, from palliative to consolidation treatment, and from advanced to early-stage neoadjuvant therapy. The development of precision immunotherapy and combination regimens offers new hope for patients. However, challenges such as irAEs and drug resistance must be addressed to fully realize the potential of immunotherapy in lung cancer treatment.

doi.org/10.1097/CM9.0000000000001116

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