Nature Medicine: Can non-small cell lung cancer be cured in the next ten years?

Recently, the Yale Cancer Center research team published a research article titled " Toward personalized treatment approaches for non-small-cell lung cancer " in Nature Medicine, summarizing and looking forward to the research progress of non-small-cell lung cancer .
The breakthrough therapies and combination therapies currently developed for NSCLC have emphasized the importance of neoadjuvant therapies and maintenance treatments in curing early-stage lung cancer
.

Nature MedicineNature Medicine Toward personalized treatment approaches for non-small-cell lung cancer Toward personalized treatment approaches for non-small-cell lung cancer

1.
Current status of lung cancer and treatment

1.
Current status of lung cancer and treatment 1.
Current status of lung cancer and treatment

The study pointed out that lung cancer, as the main cause of death of cancer patients, is expected to cause more than 1.
8 million deaths worldwide in 2021
.

Among lung cancers, 85% are subtypes of non-small-cell lung cancer (NSCLC).

Non-small cell lung cancer molecular mutation map

Molecular mutation map of non-small cell lung cancer

Since the first trial of epidermal growth factor receptor (EGFR) was launched in 2001, targeted therapy is changing the treatment plan for lung cancer
.

Nowadays, inhibitors against targets such as EGFR, ALK, RET, BRAF, ROS1, NTRK, MET and KRAS have achieved remarkable results, and many of them have become standard treatments for some patients

For patients with advanced non-small cell lung cancer with mutations in EGFR or ALK, the average survival time was less than 2 years ten years ago.
Today, with the second-generation and next-generation EGFR or ALK inhibitors, the median survival times are respectively More than 3 years and 5 years
.

For most patients with non-small cell lung cancer who do not have a clear targeted therapy option, combination chemotherapy has been the mainstream for more than 40 years, but under this therapy, the median overall survival (OS) of advanced or metastatic cancer ) Less than 2 years
.

Immunochemotherapy combination therapy is now widely used in patients with advanced or metastatic NSCLC, these patients basically have no EGFR, ALK or other driver mutations

2.
Combined immunotherapy

2.
Combination therapy of immunotherapy 2.
Combination therapy of immunotherapy

At present, a large number of early clinical studies have reported the combined application of immunotherapies, including alternative ICB, agonist costimulatory cytokines or receptors, oncolytic viruses, and cancer vaccines
.

Among them, the combination therapy of targeting CTLA-4 combined with anti-PD-1/anti-PD-L1 therapy, and TIGIT combined with anti-PD-1/anti-PD-L1 therapy has promising application prospects

Combination immunotherapy that simultaneously blocks CTLA-4 and PD-1 co-inhibitory signaling pathways has shown complementary effects in preclinical studies, and can be used to treat patients with melanoma, renal cell carcinoma, and non-small cell lung cancer
.

Two studies conducted on patients with advanced non-small cell lung cancer showed that, compared with chemotherapy alone, adding anti-CTLA-4 therapy to anti-PD-1 therapy can improve patient survival

Blocking the TIGIT and PD-1/PD-L1 pathways at the same time can enhance the expansion and function of tumor antigen-specific CD8+ T cells
.

Current studies have shown that in those tumors with high PD-L1, TIGIT combination therapy has achieved more far-reaching improvements

But generally speaking, the phase 1 and phase 2 data of the immunotherapy combination study are not ideal.
Compared with the immunotherapy combination, there is no randomized trial showing that the immunotherapy combination therapy has significantly improved
.

The limited understanding of the synergistic mechanism, the best treatment plan layout, the best treatment duration, and how to best solve the problem of acquired resistance have become major challenges for immunotherapy combination therapy

3.
Combination of targeted therapy and precision immunotherapy

3.
Combination of targeted therapy and precision immunotherapy 3.
Combination of targeted therapy and precision immunotherapy

At present, anti-VEGF drugs have been proven to have immunomodulatory effects.
Therefore, the combination of targeted therapy for tumor vasculature and immunotherapy will become a reasonable combination method
.

At the same time, small molecules targeting VEGF (VEGFRs) receptors may also enhance the activity of immunotherapy, or increase the sensitivity of tumors to immunotherapy

Diagram of overall survival of targeted therapy and immunochemotherapy, Figure a is targeted therapy, Figure b is immunochemotherapy

Diagram of the overall survival of targeted therapy and immunochemotherapy, Figure a is targeted therapy, Figure b is the overall survival of targeted therapy of immunochemotherapy and immunochemotherapy, Figure a is targeted therapy, Figure b is immunochemotherapy

In addition to treating patients with advanced NSCLC, the study mentioned that about 50% of patients with early NSCLC (limited to local disease) will not survive more than 5 years, which leaves plenty of room for improving the prognosis.
Therefore, The most effective treatment method applied to early and curable patients has always been a strategy for the treatment of lung cancer
.

In fact, recent data shows that targeted therapy and immunotherapy have significant benefits in adjuvant/neo-adjuvant therapy and maintenance therapy environments, supporting early intervention
.
Many phase 2 studies have explored neoadjuvant immunotherapy options.
These preliminary data indicate that immunochemotherapy may improve long-term clinical outcomes, including curing some patients with early-stage non-small cell lung cancer
.

The study also mentioned that the research on early lung cancer should aim at curing and further explore various combination methods
.
For example, for tumors containing high biomarkers, we can devote ourselves to the study of neoadjuvant immunochemotherapy combined with surgery or radiotherapy; for tumors driven by oncogenic genes, we can explore the combination of neoadjuvant molecular targeted therapy and postoperative treatment.
Combination: For KRAS-G12C mutant NSCLC, a combination of immunotherapy and KRAS-G12C inhibitors may produce better results in early disease treatment
.

In the past ten years, translational research and clinical research have changed the detection and treatment management of non-small cell lung cancer.
In fact, the mortality rate of non-small cell lung cancer is declining at a rate of more than 2% per year.
This result will continue to improve
.
But at the same time, the next ten years are also facing major challenges.
If you want to successfully develop a reasonable combination therapy to eradicate tumors to the maximum, a major challenge will be to apply powerful predictive biomarkers to develop individualized and clear strategies for each patient.
We look forward to more major advances in the treatment of non-small cell lung cancer in the next decade!

Original source:

Original source:

Wang, M.
, Herbst, RS & Boshoff, C.
Toward personalized treatment approaches for non-small-cell lung cancer .
Nat Med 27, 1345–1356 (2021).
https://doi.
org/10.
1038/s41591-021 -01450-2.

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