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First-line dual immunotherapy for advanced NSCLC with high TMB has survival benefit

First-line dual immunotherapy for advanced NSCLC with high TMB has survival benefit. In phase I clinical trials, nivolumab combined with ipilimumab showed significant efficacy, and tumor mutational burden (TMB) has also become a potential predictor of efficacy. CheckMate 227 is an open-label phase III clinical study, which aims to explore the efficacy of a dual immune combination regimen (nivolumab combined with ipilimumab) in the treatment of high TMB (≥10 mutations/mb, mut/mb) advanced non-small cell lung cancer (NSCLC) .

Guide

PD-1 monoclonal antibody combined with chemotherapy has been proven to prolong the survival of advanced non-small cell lung cancer (NSCLC), but the status of dual immune combination therapy in advanced NSCLC is still inconclusive. Recently, the results of the Phase III study CheckMate 227 were officially published in the journal NEJM, suggesting that patients with advanced NSCLC with high tumor mutation burden (TMB) received nivolumab combined with ipilimumab as the first-line immunotherapy. PFS is significantly better than chemotherapy and has nothing to do with PD-L1 expression. . This IO treatment newsletter invited Professor He Zhiyong, director of the 12th District of the Department of Thoracic Oncology, Fujian Cancer Hospital and member of the CSCO Immunotherapy Expert Committee, to comment on the study.

Research purposes

Research method

The CheckMate 227 study enrolled patients with advanced or relapsed NSCLC who had not received chemotherapy in the past. The research is divided into 3 parts, the first part is designed as follows:

Part 1a: In patients with high PD-L1 expression (≥1%), compared with chemotherapy, the efficacy and safety of nivolumab combined with ipilimumab and nivolumab monotherapy.

Part 1b: In patients with PD-L1 expression <1%, compared with chemotherapy, the efficacy and safety of nivolumab combined with ipilimumab, and nivolumab combined with chemotherapy.

At the beginning of the CheckMate 227 study, TMB was not used as a screening criterion and stratification factor; however, as the value of TMB as a predictive marker of efficacy has gradually been recognized by researchers, the CheckMate 227 study has been revised to indicate that in patients with high TMB The PFS benefit of dual-immune combination therapy versus chemotherapy was compared as the common primary endpoint.

Therefore, the common primary endpoints of Part 1 are: (1) PD-L1 selects the OS of the population; (2) TMB selects the PFS of the dual immune combination therapy. Secondary endpoints include: (1) patients with high TMB (≥13 mut/mb) and PD-L1 expression ≥1% received PFS with nivolumab-controlled chemotherapy; (2) patients with high TMB (≥10 mut/mb) received dual immunization Combined treatment of OS compared to chemotherapy.

Research result

Common primary study endpoint 1: PFS of patients with high TMB who received nivolumab combined with ipilimumab (dual immune combination therapy) was significantly better than chemotherapy. The 1-year PFS rate in the combined immunization group was 42.6% and that in the chemotherapy group was 13.2%; the median PFS in the two groups was 7.2 months (95% CI, 5.5-13.2) vs. 5.4 months (95% CI, 4.4-5.8) . The risk ratio (HR) of disease progression or death was 0.58 (97.5% CI, 0.41-0.81; P<0.001). The objective response rates (ORR) of the two groups were 45.3% and 26.9%, respectively.

The survival benefit of dual immunotherapy versus chemotherapy is consistent in all subgroups, including subgroups with PD-L1 expression ≥1% and <1%. The incidence of adverse events of grade 3 and above in the dual immunotherapy and chemotherapy groups were 31.2% and 36.1%, respectively.

Common primary study endpoint 2: OS data for PD-L1 selected population has not been released yet.

Secondary study endpoint 1: Patients with high TMB (≥13 mut/mb) and PD-L1 expression ≥1%, nivolumab compared with chemotherapy, no PFS benefit, HR=0.95 (0.61-1.48). Secondary study endpoint 2: Data has not been released yet.

Analysis conclusion

For patients with advanced NSCLC with high TMB, nivolumab combined with ipilimumab dual immunotherapy was given to PFS, which was significantly better than chemotherapy, and it was not related to the expression of PD-L1. The results of the study confirm the status of the first-line dual-immune combination therapy for advanced NSCLC, and at the same time confirm that TMB can be used as a predictor of efficacy to screen benefiting groups.

Expert Reviews:

The CheckMate 227 study is the first phase III clinical study of dual immunotherapy (nivolumab+ipilimumab) for advanced NSCLC reported so far. With better curative effects and controllable side effects, dual immune combination therapy is expected to become the first-line treatment option for advanced NSCLC in the future; at the same time, dual immune combination therapy is also expected to be effective in improving the efficacy of immune checkpoint inhibitors. way.

The positive result is that TMB can be used as a predictive marker for the efficacy of dual-immune combination therapy.

Previous large-scale immunotherapy clinical studies (including BIRCH studies, POPLAR studies, etc.) have shown that TMB is a biomarker independent of immunophenotype. In this study, FoundationOneTM platform was used for TMB detection. The panel includes 324 cancer-related genes. The predictive value of TMB in the dual-immune combination therapy in this study is independent of the expression status of PD-L1.

Dual immunotherapy (CTLA-4 antibody + PD-1 antibody) involves the inhibitory signal of T cells at two different stages of activation and effect. CTLA-4 is up-regulated through a complex mechanism, and competitively binds CD80 (B7-1) and CD86 (B7-2) molecules with CD28, inhibits costimulatory signals, and plays a role in immune activation. After PD-1 binds to its ligands PD-L1 and PD-L2, it plays a role in the immune response stage. From a mechanism perspective, the higher the TMB, the easier it is to produce neoantigens that are immunogenic and trigger T cell responses.

Previous studies have confirmed that TMB can reflect the status of TNB (tumor neoantigen burden). Only neoantigens produced by tumor mutations can be processed by antigen-presenting cells (APC), bind to MHC-1, and then bind to T cell receptors (TCR) to maintain the first signal, and CD28-B7-1/B7-2 The strength of the second signal is modulated by the first signal. The same ligand (B7-1/B7-2) will have different effects after binding to different receptors CTLA-4 and CD28.

However, Part 1 of the CheckMate 227 study still has a lot to think about.

1. Can tumors with high TMB expression but lack of immune cell infiltration (“cold tumors”) also benefit from dual immunotherapy?

In this study, TMB and PD-L1 targeting tumor cells are used as stratification factors. However, anti-tumor immunity, especially dual-immune combination therapy, not only needs to consider tumor cells themselves, but also the immune microenvironment of tumors.

CTLA-4 antibody can regulate CD8+ T cells, Th1 cells and Treg cells, with multiple effects; CTLA-4 antibody can transform weak spontaneous immune responses into powerful immune responses that inhibit tumors. Compared with PD-1/PD-L1 antibody, CTLA-4 antibody changes the body’s immune response state, thereby improving the effectiveness of other treatments. CTLA-4 antibody can promote the infiltration of CD8+ T cells, transforming “cold tumors” into “hot tumors”, making the latter express PD-L1 molecules. At this time, combined with PD-1/PD-L1 antibodies, it is possible to achieve ” The role of 1+1>2″ is also the theoretical basis of the dual immune combination.

2. Why is the result of nivolumab single-agent control chemotherapy negative?

In the TMB+ (≥13 mut/MB) PD-L1+ patient population, nivolumab does not have the benefit of PFS compared to chemotherapy. From the median PFS value, it was 4.2 months for the nivolumab monotherapy group and 5.6 months for the chemotherapy group. At 6 months, the PFS curve crossed, and the 1-year PFS rate of nivolumab vs. chemotherapy was 24% vs. 17%. This result once again verified that single-agent immunotherapy has a long onset time, and PFS may not benefit.

After the publication of the CheckMate 026 study comparing advanced first-line nivolumab vs. chemotherapy, a retrospective analysis found that the ORR and PFS results of nivolumab single agent in patients with high TMB expression were significantly better than platinum-based chemotherapy. The mPFS was 9.7 months vs. 5.8 months. Why in CheckMate 227, TMB(+) PD-L1(+), a group of patients who are theoretically more likely to benefit from single-agent immunotherapy, get negative data? The original text did not mention the inconsistency between this result and previous research, and the possible reasons. Considering that the TMB data of CheckMate 026 is a retrospective analysis, we speculate that the post-hoc analysis of the TMB high/low subgroups may be biased.

3. Can TMB be combined with PD-L1 as a predictive marker for immunotherapy?

Although the efficacy reported in this study is outstanding, and the value of TMB in predicting efficacy has been further confirmed, due to the relatively new model of dual-immune therapy, markers and evaluation systems for predicting the efficacy of immunotherapy are still lacking. TMB and PD-L1 are currently the most reported markers that can predict the efficacy of immune checkpoint therapy. Although the early studies did not directly compare the relationship between the two, some studies have begun to explore the potential connection between the two.

Most current studies tend to believe that TMB status has nothing to do with PD-L1 expression level. This study also found that patients with high TMB can benefit from dual immunotherapy. This benefit is not different in patients with PD-L1≥1% and PD-L1<1%. This also shows that the status of TMB and PD -The expression level of L1 is irrelevant. Considering that the CheckMate 227 and KEYNOTE-189 studies respectively explored the relationship between the expression level or status of TMB and PD-L1 and the efficacy, this also shows that the importance of the two in the selection of immune checkpoint inhibitor treatment options is becoming more and more prominent.

Further research found that the combination of TMB and PD-L1 will have a greater effect in predicting efficacy. Whether immunotherapy combined with chemotherapy can become a treatment option depends on the release of TMB-related data in subsequent studies. Is it currently possible to make a selection with reference to the following flowchart? (1) Patients with high TMB/high PD-L1 can choose pembrolizumab, and whether to choose dual-immune combination therapy needs to wait for the final data. (2) Patients with high TMB/low PD-L1 can choose nivolumab+ipilimumab. (3) Patients with low TMB/high PD-L1 can choose chemotherapy or pembrolizumab. (4) Choose chemotherapy for patients with low TMB/low PD-L1. However, this is only our conjecture, maybe it’s just the tip of the iceberg for the blind.

4. How to set the cutoff value of TMB?

It is undeniable that after PD-L1, TMB has become a potential marker for predicting immune checkpoint therapy. However, similar to PD-L1 detection, TMB also has a series of problems such as detection methods, test specimens, interpretation standards and cut-off value settings. For example, the cut-off value of the high TMB population in the dual-immune combination therapy model in this study was set to ≥10 mut/mb; the cut-off value of nivolumab single-drug was set to 13 mut/mb. In published clinical studies exploring the predictive value of TMB and PD-L1, the cut-off value of TMB was set to 8.5 (SNVs/Mb). All these suggest that the setting of the TMB cut-off value is likely to be one of the main factors that determine that TMB will become a reliable marker for predicting the efficacy of immune checkpoint therapy. Furthermore, in specific clinical practice, if the sample size of the tissue is not enough, whether ctDNA can be used to detect TMB is also a question that needs to be considered in future clinical testing of TMB status.

5. What is the first choice for chemotherapy combined with immunotherapy and dual immune therapy?

In this study, for people with high TMB (≥10 mut/mb), the 1-year PFS rate and ORR rate of dual-immune therapy for advanced NSCLC were 42.6% and 45.3%, respectively, suggesting that dual-immune therapy can become advanced NSCLC The potential for first-line treatment. As the current pembrolizumab combined with pemetrexed/carboplatin regimen has been approved by the FDA for the first-line treatment of advanced non-squamous NSCLC, and the research data of KEYNOTE-189 has just been published, therefore, in the current and future treatment options, there is no For advanced NSCLC patients with driving gene mutations, whether the chemotherapy combined immunotherapy mode or the dual immune combined treatment mode is preferred has also become a clinical issue that needs to be considered.

In the KEYNOTE-189 study, the 1-year PFS rate and ORR rate of immunotherapy combined with pemetrexed/platinum were 34.1% and 47.6%, respectively. Numerically speaking, the ORR of the two modes is not much different (dual immune combination therapy vs immunotherapy combined chemotherapy, respectively 45.3% vs 47.6%), but it should be emphasized that the ORR rate of 45.3% can only represent the high TMB population The 47.6% ORR brought by immunotherapy combined with chemotherapy refers to the non-squamous NSCLC patient population.

In terms of third-degree or fourth-degree toxic side effects, the incidence of dual immunotherapy combined therapy was 31.2%, and the incidence of immunotherapy combined with chemotherapy was 67.2%, and dual immune combined therapy was superior in side effects. In the KEYNOTE-189 study, the ORR of the subgroup of patients with PD-L1≥50% receiving immunotherapy combined with chemotherapy can reach 61.4%, so the current efficacy and side effects alone may not be able to make a reasonable difference between the two s Choice.

Of course, since the enrolled populations and baseline characteristics of the two studies are not the same, direct comparison of the figures is meaningless. If you want to answer this question, you may need the results of Part 1b of the CheckMate 227 study to tell us that for patients with PD-L1<1%, whether the dual immune combination therapy should be the first choice or nivolumab + chemotherapy.

6. Cerebral Atherosclerosis

It is the pathological basis of cerebrovascular disease. Due to the thick intima of cerebral arteries and stenosis of the lumen, the blood supply to the brain is insufficient. The microthrombus in the internal carotid atherosclerotic plaque can cause cerebral embolism.

7. Others such as: obesity, eating fat, hyperlipidemia, excessive smoking and alcohol addiction, irritability, low physical activity, congenital cerebral artery malformation and cervical spondylosis often dizzy.

It is generally believed that if a person has several predisposing factors at the same time, the risk of cerebrovascular disease will increase.