The WU-KONG6 study was honored in the 2022 ESMO ESMO Sulvotinib Strength, Attacking the EGFR 20 Exon Insertion Mutation

preface

EGFR 20 exon insertion mutation is the most common subtype of EGFR rare mutation, due to the previous multiple treatment methods, the treatment of EGFR 20 exon insertion mutation advanced non-small cell lung cancer (NSCLC) is still a major problem
facing the clinic.
At present, the drug for the insertion mutation of EGFR exon 20 is under continuous research and development, and its Chinese innovative drug "suvoltinib" has become a "new top stream"
with eye-catching data.
This year's European Society for Internal Oncology (ESMO) conference announced the results
of the China Registered Study (WU-KONG6) of EGFR 20 exon insertion mutation in patients with EGFR 20 exon insertion mutation (WU-KONG6) for the failure of systematic therapy.
On this occasion, Professor Zhou Chengzhi of the First Affiliated Hospital of Guangzhou Medical University, Professor Tang Kejing of the First Affiliated Hospital of Sun Yat-sen University and Professor Fang Wenfeng of the Cancer Prevention and Control Center of Sun Yat-sen University were invited to comment on the research results of WU-KONG6 and its significance
for clinical practice.

Ride the wind and waves, and win consecutive battles

The post-line treatment of ORR with suvoltinib is close to 60%, which is expected to revolutionize the treatment pattern of EGFR 20 exon insertion mutant advanced NSCLC

Professor Zhou Chengzhi

The First Affiliated Hospital of Guangzhou Medical University

So far, a variety of TKI drugs targeting EGFR mutations have been introduced, and the popularity of these targeted drugs has greatly improved
the treatment level of EGFR mutation-positive NSCLC.
However, the EGFR 20 exon insertion mutation in the EGFR signaling pathway is resistant to existing first- and second-generation EGFR-TKIs, and third-generation EGFR-TKI has only shown some efficacy in retrospective studies with case reports or small sample sizes, and no prospective studies have been conducted
.

The EGFR 20 exon insertion mutation is a "hard bone" in the EGFR mutation, and researchers have developed
a variety of innovative drugs for this mutation type.
Chovoltinib is a highly selective EGFR-TKI independently developed in China for a variety of EGFR mutant subtypes, and this year's ESMO conference announced the results
of its first registered study (WU-KONG6).
As of July 31 this year, the efficacy analysis set of the WU-KONG6 study included 97 patients with advanced NSCLC who had previously received platinum-containing chemotherapy with the EGFR 20 exon insertion mutation and who received suvoltinib monotherapy (300 mg QD) until disease progression or intolerable toxicity develops
.
The primary endpoint of the study was the objective response rate (ORR) assessed by the Independent Review Committee (BICR) against RECIST v1.
1
.
The results showed that the overall population ORR was 59.
8%, which was excellent in ^efficacy1
.

In addition to this year's ESMO conference, suvotinib has previously reported ^2-3 in the internationally renowned journal "Cancer Discovery" with a high impact factor and other influential international conferences (such as ASCO, WCLC), and the report of this ESMO conference once again confirms the broad application prospects of suvoltinib in the future, suggesting that it is expected to change the treatment pattern
of EGFR 20 exon insertion mutation.

Directly hit the brain turn, break through the bottleneck

Suvotinib breaks the treatment dilemma of brain metastasis patients, and the ORR of brain metastases is as high as 48.
4%

Professor Tang Kejing

The First Affiliated Hospital of Sun Yat-sen University

Brain metastasis as one of the common distant metastatic sites of lung cancer, about 10% of NSCLC patients have brain metastases at the time of diagnosis, nearly 50% of NSCLC patients will have brain metastases during ^treatment4, and patients with EGFR mutations are more likely to have brain metastases than EGFR wild-type ^patients5, and studies have shown that 23%-39% of EGFR 20 exon insertion mutant NSCLC patients have brain metastases at the time of diagnosis ^6-7
。 The prognosis of patients with brain metastases is extremely poor, and the median survival time of untreated lung cancer patients with brain metastases is only 1-2 months, and the one-year survival rate is only 10%-20%⁸
.

Treatment of patients with brain metastases in lung cancer should be based on effective systematic treatment, including surgery, radiotherapy and symptomatic therapy
。 Surgery is the standard of care for patients with single brain metastases, but intracranial lesions are prone to recurrence after surgery; Whole brain radiotherapy (WBRT) can improve the local control rate of intracranial tumors to a certain extent, but it is difficult to cure intracranial lesions, the median survival of patients is limited, and WBRT is easy to cause neurocognitive function damage and reduce the quality of life of patients; Stereotactic radiation therapy (SRT) preserves neurocognitive function better than WBRT, but patients receiving SRT alone have a higher intracranial and distant failure rate than WBRT; The limited remission rate of chemotherapy for brain metastases and the high incidence of adverse effects limit their clinical use
.
The advent of molecularly targeted drugs has provided a new treatment option for NSCLC brain metastases patients with genetic mutations, and previous studies have shown that EGFR-TKI therapy has some efficacy for NSCLC brain metastases patients with EGFR-sensitive ^{mutations8-10}
.
However, EGFR 20 exon insertion mutant advanced NSCLC is more difficult
to treat in patients with associated brain metastases due to the lack of effective targeted therapies.

Although new drugs for EGFR 20 exon insertion mutation late NSCLC have been conditionally marketed overseas in recent years, their efficacy needs to be verified by large-sample size Phase III clinical trials, and the efficacy of these new drugs for baseline brain metastasis patients is still very limited, with ORR less than 20%¹¹
.
Therefore, patients with EGFR 20 exon insertion mutant advanced NSCLC urgently need more effective and safe targeted new drugs
.

As a highly selective EGFR-TKI for multiple EGFR mutant subtypes, suvotinib (DZD9008) uses a more flexible aniline-based structure at C-4 with 5-aminopyrimidine as the parent ring to make it more
affinity and selectivity for the EGFR 20 exon insertion mutation.
It has also been observed in preclinical studies that suvoltinib has good antitumor activity against brain metastasis2
.
The results of the WU-KONG6 study showed that patients with baseline EGFR 20 exon inserted into mutant advanced NSCLC received a dose of "suvoltinib 300 mg QD" with ORR of 48.
4%¹
.
The ORR of SUVOTINIB has an advantage
over similar products.
Therefore, patients with EGFR 20 exon insertion mutation NSCLC with brain metastasis may usher in new treatment options
.
At the same time, based on good ORR data, it may be possible to further explore in the future whether combination therapy models based on suvoltinib can further improve patient outcomes, such as combination radiotherapy, chemotherapy or antiangiogenic drugs
.

Take advantage of the situation and climb to new heights

Different EGFR 20 exon insertion mutant subtypes can benefit from suvoltinib

Professor Fang Wenfeng

Center for Cancer Prevention and Treatment, Sun Yat-sen University

EGFR 20 exon insertion mutation is characterized by the insertion of 1-4 amino acids between the 761 codon and the 775 codon, and different global literature reports that there are more than 100 EGFR 20 exon insertion mutation subtypes, in general, the EGFR 20 exon insertion mutation subtype is numerous and heterogeneous
。 At present, the academic community will EGFR 20 exon insertion mutation is mainly divided into "C-spiral insertion mutation" and "C-helix insertion mutation" two categories, "C-helix after insertion mutation" and "C-helix insertion mutation" is further subdivided into "proximal ring end insertion mutation" and "distal ring end insertion mutation"
.
More than 90% of the EGFR 20 exon insertion mutation subtype belongs to the "insertion mutation after the C-helix"
.

The study found that A763_Y764insFQEA subtypes of "C-helix insertion mutations" were sensitive to approved EGFR-TKI, and their efficacy and PFS were similar to those of the EGFR classic mutation subtype after ^treatment12
。 In addition, whether it is a "proximal loop insertion mutation" or a "distal loop insertion mutation", the effectiveness of existing 1-3 generations of EGFR-TKI treatment is less than 10%, mainly because the "insertion mutation after the C-helix" will cause the drug binding pocket to become small and compact, thereby preventing the effective binding of the existing 1-3 generation ^EGFR-TKI12
.
If the dose of EGFR-TKI is increased in order to increase the effectiveness of the EGFR 20 exon insertion mutation, it will bring about greater adverse effects, which in turn will seriously limit the feasibility of its clinical ^{application13}
.
Therefore, in recent years, researchers have continued to develop new drugs
that target the high affinity and high selectivity of the EGFR 20 exon insertion mutation.

At present, relatively mature new drugs are developed such as
bozitinib, Mobocertinib (TAK-788) and amivantamab (JNJ-6372).
However, multiple studies suggest that these new drugs have different efficacy for different EGFR 20 exon insertion mutant subtypes: the "proximal end insertion mutation" subtype appears to be more effective than the "distal ring insertion mutation" subtype ^14-16
.

But it is gratifying that China's self-developed innovative drug - suvoltinib has observed good anti-tumor activity in different EGFR 20 exon insertion mutation subtypes: the results of the WU-KONG6 study released at this year's ESMO conference suggest that suvoltinib has an ORR of up to 59.
8% for the overall population, of which the ORR of patients with "proximal loop insertion mutation" is 62%, and the ORR of patients with relatively poor efficacy is as high as 50%¹
。 This result is encouraging, and suvoltinib should be the first drug
in the field of EGFR 20 exon insertion mutations to target more than 50% of the ORR in the overall population.

In addition, according to preclinical research data, suvotinib has also shown good anti-tumor potential in other EGFR mutation subtypes such as EGFR-sensitive mutation, EGFR-sensitive mutation/T790M double ^mutation2
.
It is expected that more clinical data on other EGFR mutation sites will be available in the future, and it is also expected that suvoltinib can be listed as soon as possible, so as to bring good news
to the majority of patients with EGFR mutations.

Expert profile

Professor Zhou Chengzhi

Guangzhou Institute of Respiratory Health, the First Affiliated Hospital of Guangzhou Medical University, Director of the Clinical Diagnosis and Treatment Department of the National Respiratory Medicine Center, Deputy Director of the Department of Respiratory and Critical Care, Director of the Fifth Respiratory Region (Tumor Area I), and Assistant Director of the Cancer Center

• Deputy Leader of the Lung Cancer Group of the Respiratory Branch of the Chinese Medical Association

• Member of the Lung Cancer Working Group of the Respiratory Branch of the Chinese Medical Doctor Association

• Secretary General of China Respiratory Oncology Collaborative Group (CROC) and Vice Chairman of the Youth Committee

• Vice Chairman of the Expert Committee of the China Lung Cancer Early Diagnosis and Early Treatment Capacity Improvement Project

• He is a member of the CSCO Youth Committee, the Committee on Patient Education and the Special Committee on the Prevention and Treatment of Cancer in the Elderly

• He is the chairman of the Critical Cancer Committee of the Guangdong Society of Thoracic Cancer Diseases

• Chairman of Lung Cancer Branch of Guangdong Precision Medicine Applied Society

• Deputy Leader of Lung Cancer Group of Respiratory Disease Branch of Guangdong Medical Association

• Vice Chairman of Pulmonary Oncology Branch of Guangdong Medical Association

• Vice Chairman of the Medical Oncology Branch of Guangdong Medical Doctor Association

• Vice Chairman of Lung Cancer Branch and Real World Research Branch of Guangdong Clinical Medical Association

Professor Tang Kejing

Deputy Director of the Department of Respiratory and Critical Care Medicine, First Affiliated Hospital of Sun Yat-sen University, Director of the Department of Pharmacy / Secretary of the General Branch of the Party, Director of the Department of Infectious Diseases, Doctor of Medicine, Chief Physician, Doctoral Supervisor, Postdoctoral Co-supervisor

• Visiting Scholar at Vanderbilt University Medical Center, USA

• Visiting scientist at the Harold C.
  Simmons Comprehensive Cancer Center at the University of Texas Southwestern Medical Center (UTSW).
  

• Standing Committee Member of Respiratory Physician Branch of Guangdong Medical Doctor Association, Leader of Infection and Severe Illness Professional Working Group

• Standing Committee Member of Respiratory Disease Branch of Guangdong Medical Association

• Vice Chairman of Clinical Pharmacy Branch of Guangdong Medical Association

• Vice Chairman of the Respiratory and Critical Care Medicine Professional Committee of Guangdong Association of Women Physicians

• Vice Chairman of the Respiratory Disease Professional Committee of Guangdong Clinical Medical Association

• Member of the Standing Committee of the Immunotherapy Committee of the China Lung Cancer Prevention and Control Alliance

• He is a member of the Lung Cancer Working Committee of the Respiratory Physicians Branch of the Chinese Medical Doctor Association

• Director of Guangdong Clinical Trials Association (GACT/CTONG).
  

• Deputy Director of Guangdong Provincial Quality Control Center for Monitoring and Control of Drug-Resistant Bacteria

• Vice Chairman of the Lung Cancer Professional Committee of Guangdong Primary Medicine Association

• Standing Committee Member of Lung Cancer Professional Committee of Guangdong Association of Women Physicians

• He is a member of the Evidence-Based Medicine Group of the Internal Medicine Branch of the Chinese Medical Association

Professor Fang Wenfeng

Chief Physician of the Department of Internal Medicine, Affiliated Cancer Hospital of Sun Yat-sen University, Doctoral Supervisor

• "National High-level Talents Special Support Program for Young Top-notch Talents"

• "Guangdong Province Special Support Program 100 Million Young Talents of Engineering"

• "Outstanding Young Medical Talents of Guangdong Province"

• "Guangzhou Pearl River Science and Technology Rising Star"

• Member of the CSCO Non-Small Cell Lung Cancer Professional Committee

• Member of the CSCO Nasopharyngeal Cancer Professional Committee

• He is a member of the Lung Cancer Professional Committee of the Chinese Anti-Cancer Association

• Vice Chairman of the Professional Youth Committee of Nasopharyngeal Cancer of Guangdong Anti-Cancer Association

• Vice Chairman of the Precision Medicine and Molecular Diagnostics Professional Committee of Guangdong Medical Association

References: (Swipe up to read)

1.
Mengzhao Wang, et al.
Sunvozertinib for NSCLC patients with EGFR exon 20 insertion mutations: Preliminary analysis of WU-KONG6, the first pivotal study.
2022 ESMO abstract 987P.

2.
Wang M, Yang J C H, Mitchell P L, et al.
Sunvozertinib, a selective EGFR inhibitor for previously treated non-small cell lung cancer with EGFR exon 20 insertion mutations[J].
Cancer discovery, 2022, 12(7): 1676.

3.
Yang JCH, Wang M, Mitchell P, et al.
Sunvozertinib in NSCLC patients with EGFR exon 20 insertion mutations.
Presented at: 2022 World Conference on Lung Cancer; August 6-9, 2022; Vienna, Austria.
Abstract EP08.
02-029.

4.
Ouyang W, Yu J, Xu Y, et al.
Metachronous Brain Metastasis in patients with EGFR-mutant NSCLC indicates a worse prognosis[J].
Journal of Cancer, 2020, 11(24): 7283.

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Hsu F, De Caluwe A, Anderson D, et al.
EGFR mutation status on brain metastases from non-small cell lung cancer[J].
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Cardona A F, Rojas L, Zatarain-Barrón Z L, et al.
EGFR exon 20 insertion in lung adenocarcinomas among Hispanics (geno1.
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Yang G, Li J, Xu H, et al.
EGFR exon 20 insertion mutations in Chinese advanced non-small cell lung cancer patients: molecular heterogeneity and treatment outcome from nationwide real-world study[J].
Lung Cancer, 2020, 145: 186-194.

8.
Yang Yuanyuan, Han Zhigang.
Application progress of main treatment methods for brain metastases for non-small cell lung cancer[J].
Shandong Medicine, 2022.

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Shi Yuankai,Sun Yan,Yu Jinming,etc.
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Chinese Journal of Lung Cancer,2017,20(01):1-12.

11.
Janne P A, Ramalingam S S, Yang J C H, et al.
Mobocertinib (TAK-788) in EGFR exon 20 insertion (ex20ins)+ metastatic non–small cell lung cancer (mNSCLC): Treatment (tx) beyond progressive disease (PD) in platinum-pretreated patients ( pts) with and without intracranial PD[J].
2022.

12.
Yang Xue,Zhao Jun.
Clinical Research Progress on EGFR Exon 20 Insertion Mutation-positive NSCLC Therapy[J].
Chinese Journal of Lung Cancer,2022,25(05):337-350.

13.
Zwierenga F, van Veggel B, Hendriks L E L, et al.
High dose osimertinib in patients with advanced stage EGFR exon 20 mutation-positive NSCLC: Results from the phase 2 multicenter POSITION20 trial[J].
Lung Cancer, 2022, 170: 133-140.

14.
Elamin Y Y, Robichaux J P, Carter B W, et al.
Poziotinib for EGFR exon 20-mutant NSCLC: Clinical efficacy, resistance mechanisms, and impact of insertion location on drug sensitivity[J].
Cancer Cell, 2022, 40(7): 754-767.
e6.

15.
Zhou C, Ramalingam S S, Kim T M, et al.
Treatment outcomes and safety of mobocertinib in platinum-pretreated patients with EGFR exon 20 insertion–positive metastatic non–small cell lung cancer: a phase 1/2 open-label nonrandomized clinical trial[J].
JAMA oncology, 2021, 7(12): e214761-e214761.

16.
Park K, Haura E B, Leighl N B, et al.
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Journal of Clinical Oncology, 2021, 39(30): 3391-3402.

Edit: HCM

Reviewer: Fish balls

Typography: Uni

Execution: Uni