The latest research progress of six rare targets in lung cancer, one article inventory

On the research progress of targeted therapy of six rare targets, many new drugs broke out
.

Lung cancer is one of the main causes of cancer-related deaths worldwide.
In 2020, there will be about 810,000 new lung cancers and about 710,000 deaths in China [1]
.

Non-small cell lung cancer (NSCLC) accounts for 80%-85% of all lung malignancies.
The emergence of driver mutations including EGFR and ALK and their corresponding targeted drugs have brought revolutionary changes to the treatment and prognosis of advanced NSCLC [ 2]
.

In addition, with the improvement of detection technology, the targets of other rare driver genes have been gradually discovered, such as BRAF, NTRK, RET, MET, HER2, EGFR20 exon insertion mutations, etc.
The corresponding targeted drugs have been partially Approved in the clinic, although some are still in the research stage, they have achieved obvious curative effects
.

This article will summarize the progress in the diagnosis and treatment of these NSCLCs with rare mutations
.

 BRAF BRAF gene mutation occurs in lung adenocarcinoma, accounting for 1%-3% of NSCLC
.

The characteristics and treatment of different types of BRAF gene mutations are quite different
.

BRAF V600E mutation is not necessarily associated with smoking history, and can lead to more aggressive tumors and worse prognosis, and the application of BRAF inhibitors is effective [3]
.

 Recently, the "Journal of Thoracic Oncology" published data after a 5-year follow-up study.
The study included patients with BRAF V600E-mutant NSCLC who were divided into a treatment-experienced group and a treatment-naïve group, all of whom received dabrafenib + trametinib.
The results showed that the objective response rate (ORR) of the treatment-naïve cohort and the treatment-naïve cohort were 68.
4% and 63.
9%, respectively, and the median progression-free survival (PFS) was 10.
2 months and 10.
8 months, respectively.
The median overall The survival time (OS) was 18.
2 months and 17.
3 months, respectively [4]
.

On the other hand, non-V600E mutations are only found in smokers, and BRAF inhibitor treatment is ineffective [3]
.

At present, there is still a lack of effective targeted therapy drugs for patients with BRAF non-V600E mutation
.

 NTRK NTRK gene fusion mutations can occur in different tumors, especially in soft tissue sarcoma, and the incidence in NSCLC is about 3% [3]
.

At present, there are two drugs on the global market for the treatment of NTRK fusion gene solid tumors, namely larottinib and entrectinib
.

A study reporting the efficacy of larotrectinib in 11 patients with metastatic lung adenocarcinoma, 7 of whom were evaluable for efficacy, showed 1 complete response, 4 partial responses, 2 stable disease, and treatment-related adverse events.
The reaction is mainly grade 1-2
.

 Another literature reported the pooled results of 3 clinical studies (STARTRK-2, STARTRK-1, ALKA-372-001) of entrectinib in NSCLC, including 10 patients with locally advanced or metastatic NSCLC, ORR reached 70%, of which 6 patients had brain metastases before treatment, and 4 patients had intracranial lesions shrunk after treatment [5]
.

The detection of NTRK gene fusions and the emergence of TRK inhibitors have brought new light to patients with NSCLC
.

 RET RET gene fusions are more common in lung adenocarcinoma, with an incidence of about 1.
6% in Chinese [2]
.

Pratinib is currently approved by the China National Medical Products Administration (NMPA) for the treatment of adult patients with RET gene fusion-positive locally advanced or metastatic NSCLC who have previously received platinum-based chemotherapy
.

The results of the ARROW study recently published in The Lancet Oncology showed that the ORR of previously treated NSCLC patients was 61%, the median PFS was 17.
1 months, and the median OS was not reached; among patients who had not received systemic therapy before , ORR was 70%, the median PFS was 9.
1 months, and the median OS was not reached [6]
.

 MET MET pathway abnormalities include gene mutation, amplification, fusion, and protein overexpression.
In NSCLC patients, MET exon 14 skipping mutations account for about 3%-4% [7]
.

In lung sarcomatoid carcinoma, the incidence of MET exon 14 skipping mutation may be higher, reaching about 31.
8% [8]
.

 Recently, Professor Lu Shun of the Chest Hospital Affiliated to Shanghai Jiaotong University published the latest results of a phase II study in the journal "The Lancet Respiratory Medicine", showing that the MET inhibitor sivotinib has a skipping mutation in MET exon 14.
Efficacy in NSCLC patients
.

The results showed that the MET inhibitor sivotinib could bring ORR benefit and higher disease control rate and survival (OS) to patients with MET exon 14 skipping mutation NSCLC
.

At the same time, the results of subgroup analysis showed that savotinib can also benefit patients with lung sarcoid carcinoma and brain metastases[9]
.

 HER2 The mutation rate of HER2 gene in NSCLC patients is not high, only 1%-4%[3]
.

There is currently no standard treatment regimen for patients with HER2-mutated NSCLC [3]
.

 EGFR exon 20 insertion mutation The study found that EGFR20 exon insertion mutation accounted for 4.
8% of EGFR-mutant NSCLC, accounting for 2.
3% of all NSCLC patients[10]
.

For EGFR20 exon insertion mutation, as of now, no specific targeted drugs have been approved in China, and chemotherapy is the main treatment method.

.

In 2021, the U.
S.
Food and Drug Administration (FDA) formally approved mobocertinib (TAK-788) for the treatment of adult patients with NSCLC with EGFR exon 20 insertion mutations
.

The approval is based on positive results from a phase I/II trial in the platinum-based chemotherapy-pretreated patients (PPP) cohort and the EXCLAIM cohort
.

The PPP cohort included 114 platinum-pretreated NSCLC patients with EGFR exon 20 insertion mutations, and the EXCLAIM cohort included 96 treated EGFR exon 20 insertion mutation NSCLC patients
.

 The results showed that in the PPP cohort, the ORR confirmed by the independent review committee was 28%, the DCR was 78%, and the median PFS was 7.
3 months; in the EXCLAIM cohort, the ORR confirmed by the independent review committee was 25%, and the DCR was 25%.
76%, and the median PFS was 7.
3 months [11]
.

 In addition, the FDA also approved a bispecific EGFR/c-Met antibody, Amivantamab (JNJ-61186372), for the treatment of adult patients with NSCLC with EGFR exon insertion mutations.
It is believed that the two drugs will give the rare target EGFR exon 20.
Insertion mutation NSCLC patients bring additional benefits
.

 Prospects The development of NSCLC targeted therapy can be said to have achieved certain achievements today, and the research and development of new targeted drugs emerges one after another
.

In addition to EGFR, new rare molecular targets are constantly being detected, and corresponding targeted drugs are constantly being developed.
Clinical trials have shown exciting results and bright prospects
.

It is believed that with the deepening of research, people may redefine the role of targeted therapy in the treatment of lung cancer, and targeted therapy may eventually change the treatment mode of lung cancer, bringing hope to patients with limited treatment options
.

  Reference: [1] Sung H, Ferlay J, Siegel RL, et al.
Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries [J].
CA: a cancer journal for clinicians, 2021, 71(3): 209-249.
[2] Luo Jiawei, Wu Fengying, Zhou Caicun.
Inventory of the treatment progress of rare driver gene-positive non-small cell lung cancer [J].
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[3] Yang Guangjian, Wang Yan.
Research progress in the treatment of rare gene mutations in non-small cell lung cancer [J].
Cancer Progress, 2019, 17(12): 1371-1376, 1418.
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Phase 2 Study of Dabrafenib Plus Trametinib in Patients With BRAF V600E-Mutant Metastatic NSCLC: Updated 5-Year Survival Rates and Genomic Analysis [published online ahead of print, 2021 Aug 26].
J Thorac Oncol.
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Research progress of NTRK gene fusion and TRK inhibitor in non-small cell lung cancer[J].
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[6]Gainor JF, Curigliano G, Kim DW, et al.
Pralsetinib for RET fusion-positive non-small-cell lung cancer (ARROW): a multi-cohort, open-label,phase 1/2 study [published correction appears in Lancet Oncol.
2021 Aug;22(8):e347].
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[7] Li Guoyu, He Ming.
Non-small cell lung cancer The latest research progress of rare target targeted therapy[J].
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[8]Tong JH, Yeung SF, Chan AWH, et al.
MET amplification and exon 14 splice site Mutation define unique molecular subgroups of non–small cell lung carcinoma with poor prognosis[J].
Clinical Cancer Research, 2016, 22(12): 3048-3056.
[9]Lu S, Fang J, Li X, et al.
Once -daily savolitinib in Chinese patients with pulmonary sarcomatoid carcinomas and other non-small-cell lung cancers harbouring MET exon 14 skipping alterations: a multicentre, single-arm, open-label, phase 2 study.
Lancet Respir Med.
2021;9(10 ):1154-1164.
[10]Fang W, Huang Y, Hong S, et al.
EGFR exon 20 insertion mutations and response to osimertinib in non-small-cell lung cancer.
BMC Cancer.
2019;19(1):595 .
[11] Ramalingam SS, Zhou C, Kim TM, et al.
Mobocertinib (TAK-788) in EGFR exon 20 insertion (Ex20ins)+ metastatic NSCLC (Mnsclc): Additional results from platinum-pretreated patients (Pts) and EXCLAIM cohort of phase 1/2 study.
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