In recent years, Immune Checkpoint Inhibitors (ICIs), including anti-PD-1/PD-L1 and anti-CTLA-4, have revolutionized the field of oncology treatment, becoming a landmark event in rewriting the treatment paradigm of non-small-cell lung cancer (NSCLC). Cancer, NSCLC), and many other malignancies, has been a landmark event. Despite the encouraging antitumor effects of ICIs, the single-agent benefit population is still very limited, and most patients inevitably develop drug resistance. How to further improve the efficacy of ICIs through combination therapeutic strategies has become a new hot spot and direction in the field of immunotherapy.
To date, with the increasing number of ICIs approved by the US Food and Drug Administration (FDA) and the State Drug Administration of China (NMPA), there are numerous immune combination strategies, including immune combination with chemotherapy, combination with radiotherapy, combination with anti-angiogenic drugs, and combination with other ICIs. Previous studies have shown that chemotherapy can have synergistic anti-tumor effects with immunotherapy, and immunotherapy combined with anti-angiogenic drugs can further enhance the efficacy by improving the patient’s tumor microenvironment, TME. In addition, combinations of ICIs for different targets have been successfully developed. Although there are several immunotherapy combination strategies to choose from, which immunotherapy combination strategy is the most effective? Is there a difference in safety between the different immunotherapy combination strategies?
On April 8, 2021, the Journal of Thoracic Oncology, a leading international oncology journal, published online Professor Wang Jie, Professor Bai Hua, and PhD student Liu Lihui of the Cancer Hospital, Chinese Academy of Medical Sciences. Efficacy and Safety of First-Line Immunotherapy Combinations for Advanced Non-Small-Cell Lung Cancer: A Systematic Review and Network Meta-Analysis This study is the first meta-analysis dedicated to exploring the efficacy and safety of immunotherapy combinations for NSCLC.
The investigators included a total of
9070 first-line treated non-small cell patients and systematically compared the efficacy and safety of 10 immune combination treatment strategies using a Bayesian model as well as a frequency model, including: pembrolizumab combined with chemotherapy (pem-chemo), atezolizumab combined with chemotherapy (atezo-chemo) atezolizumab in combination with chemotherapy and anti-vascular agents (atezo-beva-chemo), camrelizumab in combination with chemotherapy (camre-chemo), tislelizumab in combination with chemotherapy (tisle-chemo), sintilimab in combination with chemotherapy (sint-chemo), and nivolumab in combination with ipilimumab (nivo-ipi), nivolumab in combination with ipilimumab and chemotherapy (nivo-ipi-chemo), durvalumab in combination with tremelimumab (durva-treme), and durvalumab in combination with tremelimumab and chemotherapy (durva-treme-chemo).
For overall survival (Overall Survival, OS), immune combination therapy was superior to standard platinum-containing two-drug chemotherapy. Among them, the combination strategy of sinti-chemo as well as pem-chemo showed the best OS benefit, with risk ratios (Hazard Ratio, HR) of 0.59 (95% CI: 0.45-0.77) and 0.61 (95% CI: 0.53-0.69). In addition, anti-PD-1 antibody-based combination strategies demonstrated better OS benefit compared to both anti-PD-L1 and anti-CTLA-4-based combination strategies. Atezo-beva-chemo provided the best PFS benefit (HR: 0.45, 95% CI: 0.36-0.55), followed closely by sint-chemo (HR: 0.51, 95% CI: 0.44-0.60) and pem-chemo (HR: 0.54, 95% CI: 0.49-0.61). Similarly, the combination strategy of anti-PD-1 antibodies was superior compared to the combination strategy of anti-PD-L1, while there was no significant difference between the different combination strategies of anti-PD-1 antibodies in terms of providing PFS benefit. The results for Objective Response Rate (ORR) were similar to those for PFS, with atezo-beva-chemo still providing the best objective remission rate (HR: 0.23, 95% CI: 0.12-0.42),
Followed by pem-chemo (HR: 0.38, 95% CI: 0.26-0.54).
In terms of safety, the investigators explored the incidence of adverse events (Adverse Events, AEs) of any grade and those greater than or equal to grade 3 in different immunization combination strategies. Among all immune combination strategies, the incidence of AEs was significantly lower with nivo-ipi and durva-treme than with standard chemotherapy; AEs were higher with immune combination chemotherapy than with standard chemotherapy, especially in combination with the antivascular agent bevacizumab (atezo-beva-chemo). In contrast, grade 3 AEs occurred relatively less with pem-chemo as well as sint-chemo in the immune-combination chemotherapy strategy. In addition, the incidence of treatment-related adverse reactions varied widely among the different combination strategies, with durva-treme-chemo causing the highest probability of fatigue, nausea, anemia, vomiting, diarrhea, and rash; the incidence of immune-related adverse reactions was relatively similar among the different combination strategies.
The investigators ranked the efficacy and safety of all immune combination strategies for four metrics: OS, PFS, ORR, and greater than or equal to tertiary AEs, allowing readers and clinicians to more clearly understand where each combination strategy ranks in the different metrics. In terms of providing the best OS, sint-chemo ranked first, pem-chemo ranked second, and nivo-ipi-chemo ranked third; in terms of providing the best PFS, atezo-beva-chemo ranked first, sint-chemo ranked second, and pem-chemo ranked third; in terms of providing the best ORR, the In terms of safety, nivo-ipi caused the fewest AEs, followed by durva-treme and pem-chemo. In summary, considering both efficacy and safety, the investigators recommend pem-chemo as the preferred strategy for immune combination therapy. as the preferred strategy for immune combination therapy.
In this study, the investigators also performed an in-depth subgroup analysis based on PD-L1 expression, histopathological type, and the National Comprehensive Cancer Network’s (NCCN) recommended immune combination strategy, respectively, to provide additional clinical guidance. For patients with negative PD-L1 expression (PD-L1 <1%), the combination of nivo-ipi-chemo provided the best OS as well as PFS, whereas for patients with positive PD-L1 expression (PD-L1 ≥1%), pem-chemo and sint-chemo provided the best OS as well as PFS, respectively. PFS.
The researchers also noted that the current coverage of black ethnicity in immunotherapy clinical studies is low, which is not conducive to future studies related to patient population screening; the strategy of pembrolizumab in combination with chemotherapy and antivascular agents may provide better survival benefit for patients with NSCLC. While future clinical trials comparing head-to-head pembrolizumab in combination with chemotherapy and antivascular agents (pem-beva-chemo) versus pembrolizumab in combination with chemotherapy (pem-chemo) and comparing nivolumab in combination with ipilimumab (nivo-ipi) versus nivolumab clinical trials combining ipilimumab and chemotherapy (nivo-ipi-chemo) can provide more direct evidence.