Editor's Note: Since the FDA approval of the first lung cancer immunotherapy regimen in 2015 based on the CheckMate-017 and 057 studies, lung cancer immunotherapy has evolved significantly over the past decade, becoming the first-line standard of care for patients with driver mutation-negative non-small cell lung cancer (NSCLC). However, as evidence accumulates and clinical experience grows, some issues continue to stir debate. During the recent "2024 CSCO Lung Cancer Standardized Treatment Workshop," Oncology Frontier interviewed Dr. Meiqi Shi from Jiangsu Cancer Hospital to discuss key topics such as the choice of immunotherapy, treatment for brain metastases, immunotherapy rechallenge, and management of adverse events.

1. Differences in PD-1 and PD-L1 Inhibitors: Clinical Considerations

Oncology Frontier: Immunotherapy has become the standard treatment for patients without driver mutations. Do you see differences between PD-1 and PD-L1 inhibitors, and what role do PD-L1 expression and other biomarkers play in guiding therapy?

Dr. Meiqi Shi: PD-1 and PD-L1 inhibitors differ in terms of mechanism, clinical efficacy, and safety. PD-1 inhibitors act on the PD-1 receptor expressed on T cells, whereas PD-L1 inhibitors primarily bind to the PD-L1 ligand on tumor cells. Although there is some PD-L1 expression on T cells and macrophages, it is mainly concentrated on tumor cells. Thus, the sites of action differ between the two types of inhibitors.

When PD-L1 on tumor cells binds to PD-1 on T cells, it suppresses T cell activity and blocks the immune system’s attack on tumors. PD-1 or PD-L1 inhibitors aim to disrupt this immune escape mechanism, reactivating T cells to target tumor cells.

However, in clinical practice, PD-1 inhibitors often appear to have a slight advantage in efficacy, particularly in the treatment of advanced, driver mutation-negative NSCLC. Studies like KEYNOTE-407 and KEYNOTE-189 have demonstrated that PD-1 inhibitors provide long-term survival benefits, with pembrolizumab gaining widespread use and even being referred to as the “king of immune drugs.” Recently, another PD-1 dual-target drug (PD-1/VEGF) showed superior progression-free survival (PFS) in head-to-head comparison with another PD-1 inhibitor (11.4 vs. 5.82 months), suggesting it could surpass current standards.

Although there are no head-to-head studies comparing PD-1 and PD-L1 inhibitors, a meta-analysis published in JAMA Oncology in 2020 indicated that PD-1 inhibitors generally offer better PFS and overall survival (OS). In terms of safety, PD-L1 inhibitors are theoretically less likely to overstimulate the immune system, as they act on tumor cells rather than directly on T cells. Meta-analyses published in Future Oncology in 2021 supported this, showing a lower risk of immune-related adverse events (irAEs) with PD-L1 inhibitors compared to PD-1 inhibitors.

Regarding biomarkers, PD-L1 expression plays a crucial role in guiding immunotherapy for NSCLC. High PD-L1 expression often correlates with better response to immunotherapy, making monotherapy sufficient for patients with high PD-L1 expression. For patients with low or negative PD-L1 expression, combination therapy, such as chemotherapy combined with immunotherapy, may be necessary—especially for those with high tumor burden, brain metastases, or pleural effusion.

In conclusion, PD-1 and PD-L1 inhibitors each have unique advantages and characteristics in terms of efficacy, safety, and clinical strategy. Treatment decisions should be personalized based on patient characteristics and PD-L1 expression levels.

2. Immunotherapy for Patients with Brain Metastases

Oncology Frontier: Brain metastases are common among lung cancer patients. What is your view on the value of immunotherapy in treating patients with brain metastases?

Dr. Meiqi Shi: I believe immunotherapy is also valuable in treating patients with brain metastases. For NSCLC, particularly non-squamous NSCLC, we first need to distinguish between patients with and without driver mutations. Immunotherapy or immunotherapy combined with chemotherapy is the standard treatment for patients without driver mutations, with the choice of monotherapy or combination therapy guided by PD-L1 expression levels.

For patients with driver mutations, small-molecule TKIs are the standard of care. Brain metastases are common in lung cancer, and during the chemotherapy era, treatment was particularly challenging due to the blood-brain barrier. Radiation therapy was often the preferred option for local treatment. However, with the advent of targeted and immunotherapy, especially for driver mutation-positive patients, numerous studies have shown that TKIs perform well both intracranially and extracranially.

For driver mutation-negative patients with brain metastases, clinical trials have shown that both monotherapy and combination therapy are effective in controlling brain lesions. This demonstrates that patients with brain metastases can also benefit from immunotherapy. While the mechanisms remain under study, various hypotheses suggest immune cell activation outside the brain, followed by penetration through the blood-brain barrier, or direct activation of the intracranial immune system. Regardless of the mechanism, immunotherapy has shown good efficacy in patients with brain metastases.

3. Rechallenge in Immunotherapy

Oncology Frontier: Immunotherapy rechallenge is a topic of debate. In which patients would you consider an immunotherapy rechallenge?

Dr. Meiqi Shi: Rechallenge is undoubtedly a hot topic. Initially, immunotherapy was used as a later-line treatment. However, with growing evidence, it is now clear that first-line immunotherapy provides better outcomes than later-line therapy in driver mutation-negative advanced NSCLC. This is supported by ample clinical data.

When resistance develops after first-line immunotherapy, second-line treatment becomes a challenge. In clinical practice, we often face three strategies: discontinuing immunotherapy, maintaining the original drug across treatment lines, or switching to a different immunotherapy drug. Given the importance of continuous stimulation of immune cells for sustained anti-tumor effects, maintaining or rechallenging immunotherapy is highly anticipated.

“Rechallenge” can mean reintroducing immunotherapy after a period of discontinuation due to disease progression. While expectations are high, most trials have not succeeded in challenging current standard second-line therapy, which remains docetaxel-based combinations. This was reflected in this year’s expert consensus in China, which recommended docetaxel-based combinations for patients with immunotherapy resistance.

Various rechallenge strategies, such as dual immunotherapy combinations and TKI combinations, continue to be explored. With further research, we hope to gain clearer evidence for the role of immunotherapy rechallenge.

4. Managing Immune-Related Adverse Events and Multidisciplinary Teamwork

Oncology Frontier: Immune-related adverse events can affect multiple systems. How do you manage common immune-related adverse events, and what role does multidisciplinary collaboration play?

Dr. Meiqi Shi: Since the advent of immunotherapy, we have recognized that its adverse events differ significantly from those of chemotherapy and targeted therapy. While traditional side effects are predictable, immune-related adverse events are often complex and elusive. Predicting adverse events in immunotherapy is challenging, and they can occur in any organ.

Multidisciplinary team (MDT) collaboration is vital in managing immune-related adverse events. At specialized cancer hospitals, we maintain close connections with respiratory, cardiology, dermatology, and other departments to address these issues. Ideally, establishing dedicated MDT teams would be the most effective solution, allowing specialists to work together to manage these events comprehensively.

Dr. Meiqi Shi Chief Physician, Professor, and Master’s Supervisor Subspecialty of Lung Cancer, Department of Oncology, Jiangsu Cancer Hospital/Research Institute for Cancer Prevention and Control Expertise: Treatment of advanced cancers, specializing in medical treatment of lung cancer, having participated in nearly 80 international and domestic multi-center clinical drug trials for lung cancer, and published over 100 papers. The highest impact factor of SCI articles published as the first author is 32.976. Recipient of two Second Prizes in New Technology Introduction from the Jiangsu Provincial Health Department. Appointments include:

• Standing Committee Member, Oncology Medicine Branch, China International Medical Exchange Promotion Association
• Standing Committee Member, Thoracic Oncology Branch, China International Medical Exchange Promotion Association
• Member, NSCLC and SCLC Expert Committees, CSCO
• Member, Clinical Research on Anticancer Drugs Committee, Chinese Anti-Cancer Association
• Vice Chair, Pan-Yangtze River Delta Thoracic Tumor Alliance
• Standing Committee Member, Molecular Markers Collaborative Group for Pulmonary Nodules, Tumor Markers Branch, Chinese Anti-Cancer Association
• Vice Chair, Lung Nodule and Lung Cancer MDT Committee, Jiangsu Research Hospital Society
• Standing Committee Member, Lung Cancer Professional Committee, Jiangsu Anti-Cancer Association
• Member, Pulmonary Rehabilitation Professional Committee, Jiangsu Association of Rehabilitation Medicine
• Vice Chair, Lung Cancer Group, Oncology Committee, Jiangsu Medical Association
• Member, Pulmonary Cancer Group, Respiratory Diseases Branch, Jiangsu Medical Association
• Member, Nanjing Medical Association Pulmonary and Tuberculosis Diseases Committee
• Member, International Lung Cancer Association
• Member, ASCO