【WCLC2021】Professor Zhou Qing: EGFR Exon20ins NSCLC re-focused, and released Amivantamab for the first time in the new therapeutic field!

*Only for medical professionals to read for reference.
Experts from various countries focus on EGFR Exon20ins NSCLC diagnosis and treatment.
Johnson & Johnson released new data on Amivantamab monotherapy c-MET and combined chemotherapy for EGFRm+ for the first time! In recent years, the incidence of lung cancer has continued to increase.
In 2020, the incidence and mortality of lung cancer in China will continue to increase.
Among them, NSCLC is the most common pathological type of lung cancer, accounting for about 80%-85% of the total number of lung cancer patients[1]
.

As the level of molecular diagnosis and treatment continues to improve, targeted drugs are playing an increasingly important role in the treatment of lung cancer
.

The current World Lung Cancer Conference will be held in the form of an online conference from September 8 to 14, 2021
.

Numerous blockbuster studies related to NSCLC targeted therapy were published at the conference
.

This time the "medical community" invited a well-known expert in the field of lung cancer treatment, Professor Zhou Qing, Dean of the Cancer Hospital of Guangdong Provincial People's Hospital, to bring us insights and thoughts on the progress of the diagnosis and treatment of non-small cell lung cancer in the 2021 WCLC
.

In recent years, with the advancement of molecular detection technology, lung cancer driver genes have gradually been more comprehensively recognized and understood, and more and more lung cancer driver gene mutations with lower frequency have received widespread attention
.

At present, the treatment methods, accessibility of drugs and the therapeutic effects of existing drugs for patients with rare gene mutations in lung cancer are far worse than those of patients with common gene mutations
.

EGFR Exon20ins is a rare mutation of NSCLC, accounting for about 2.
1% of all NSCLC
.

In China, the incidence of EGFR Exon20ins accounts for approximately 2.
3% of all NSCLC
.

However, the existing EGFR-TKI, chemotherapy and immunotherapy have limited clinical benefits for NSCLC patients carrying EGFR Exon20ins
.

Patients are plagued by diseases and have urgent clinical treatment needs
.

The WCLC conference also released a number of encouraging new developments in the field of EGFR Exon20ins diagnosis and treatment
.

EGFR Exon20ins molecular test-tissue biopsy or ctDNA test? Accurate diagnosis and identification of EGFR Exon20ins is a prerequisite for treatment
.

Professor Zhou Qing said that traditionally the diagnosis of EGFR Exon20ins can detect the mutation of the gene from DNA extracted from living tissues or blood tumor cells, namely tissue biopsy and ctDNA detection.
Compared with traditional tissue biopsy, body fluid biopsy is more convenient and more convenient for patients.
In terms of less trauma, the risk is lower
.

For complete information on tumor burden, body fluid biopsy can also provide more, and multiple tests are also possible
.

However, due to the lysis of white blood cells after the blood is isolated, the DNA dilution of the target ctDNA, etc.
, also make the test and the acquisition of specimens more difficult
.

There are many methods for ctDNA analysis, such as real-time or digital PCR to detect specific known gene mutations, and NGS detection that can detect more gene mutations in multiple genes at once
.

The progress of genetic testing technology will undoubtedly promote the precise identification of patients with rare mutations in NSCLC, and eventually more patients can benefit from it
.

A confirmatory study of Amivantamab companion diagnosis was reported at this year's WCLC annual meeting to detect EGFR Exon20ins mutations
.

The bridging test [2] clinically verified two potential NGS companion diagnostic methods: Guardant360CDx and Oncomine Dx targeted detection methods (ODxT detection), which are used to detect EGFR Exon20ins mutation subtypes
.

Guardant360CDx: Analyze ctDNA in peripheral blood, use high-throughput hybridization targeted capture technology ODxT detection: extract FFPE tumor tissue DNA for analysis, use high-throughput parallel sequencing technology Figure 1 Guardant360 CDx technology and Oncomine Dx Target Test detection The main goal of the technical research is in the population whose efficacy is observed in the CHRYSALIS study [the population treated with platinum-containing chemotherapy, who received the recommended dose of Amivantamab Phase 2 clinical study (RP2D), n=81], for the two types of NGS detected The efficacy of patients with EGFR Exon20ins mutation was compared
.

The primary endpoint is the objective response rate (ORR) assessed by the Independent Review Committee (BIRC), and the secondary endpoint is the duration of response (DOR) from the independent imaging evaluation (IRC)
.

The results of the study show that the results of the two NGS detection methods are highly consistent with the CHRYSALIS clinical study, and both can accurately detect EGFR Exon20ins mutant NSCLC, with a positive predictive value (PPV) of 100%; the Guardant360CDx negative predictive value (NPV) based on plasma samples is 99.
6%, NPV based on ODxT of tissue samples was 99.
9%
.

Figure 2 CTAs and Guardant360CDx and ODxT test results are highly consistent.
The primary endpoint of the study showed that NSCLC patients with EGFR Exon20ins detected by Guardant360CDx and ODxT, after Amivantamab treatment, ORR were 39% and 46%, respectively, compared with the CHRYSALIS study The ORR results are consistent
.

Figure 3 Comparison of total remission rate and clinical benefit rate of EGFR 20ins NSCLC patients detected by CTAs, Guardant360CDx and ODxT.
Therefore, whether it is Guardant360CDx based on plasma samples or tissue-based ODxT detection, it provides accurate, comprehensive and complementary methods to identify For patients with EGFR Exon20ins, the U.
S.
Food and Drug Administration (FDA) has approved Guardant360CDx as a companion diagnosis for Amivantamab
.

Professor Zhou Qing emphasized that comparing the detection of tumor tissue samples with plasma ctDNA detection, we should see the advantages and disadvantages of its method.
According to the actual clinical situation and the needs of diagnosis and treatment, it can be used flexibly to truly play the greatest role of the detection method, so that patients can obtain Benefit
.

Solving the dilemma of EGFR Exon20ins NSCLC treatment-CHRYSAILS study provides a new strategy Professor Qing Zhou said that patients with EGFR Exon20ins mutant NSCLC have always received poor efficacy in traditional chemotherapy and targeted therapy
.

At this year’s WCLC conference, a retrospective real-world study explored the efficacy of immune checkpoint inhibitors in patients with EGFR Exon20ins NSCLC and wild-type NSCLC[4].
The main research endpoint is the real-world mid-to-post-line treatment time (Real world time to next treatment)
.

In the Flatiron Database of the United States (2015-2020), 16786 wild-type NSCLC patients and 192 EGFR Exon20ins NSCLC patients have received immune checkpoint inhibitor therapy, and the number of patients that can be used for efficacy evaluation is 5365 and 5365 respectively.
59 cases
.

The results showed that the most commonly used first-line treatment for the two groups were platinum-containing chemotherapy, and immune checkpoint inhibitors were often used for second-line or third-line treatment
.

In addition, among patients who were initially treated with immune checkpoint inhibitors, compared with wild-type NSCLC patients, EGFR Exon20ins NSCLC patients had a shorter time to posterior treatment (TTNT) and increased the risk by 58%
.

This result suggests that the clinical benefit of immune checkpoint inhibitors for EGFR Exon20ins NSCLC is limited, and there is an urgent need for new targeted drugs to improve patient survival benefits
.

Figures 4 and 5 EGFR Exon20ins NSCLC and wild-type NSCLC patients respond to immune checkpoint inhibitor therapy.
Because traditional chemotherapy, immunotherapy and TKIs are not effective in the treatment of EGFR Exon20ins, the performance of Amivantamab in patients with rare mutations in advanced NSCLC is of particular concern
.

The data results of CHRYSAILS study cohort D announced at the 2020WCLC conference are particularly exciting
.

The CHRYSAILS study [5] is a phase I/Ib study aimed at evaluating the safety and efficacy of Amivantamab in the treatment of patients with EGFR mutation or MET mutation NSCLC
.

The study designed multiple cohorts, in which cohort D included patients with EGFR Exon20ins who had failed platinum-containing chemotherapy treatment to evaluate the efficacy and safety of Amivantamab in the subsequent line
.

The results of the study showed that the overall response rate was 40%, the median duration of response was 11.
1 months, the CBR was 74%, the median progression-free survival (mPFS) was 8.
3 months, and the median overall survival (mOS) was 22.
8 months.

.

In addition, Amivantamab has also been confirmed to be effective for Exon 20ins with different insertion regions
.

Table 1 Amivantamab: BICR assessment efficacy Figure 6 NGS with ctDNA identified 25 different EGFR Exon20ins variants from 63 evaluable patient samples (Amivantamab: BICR assessment efficacy) Figure 7 Amivantamab: duration of disease remission and clinical treatment outcome The mechanism of action determines the efficacy of the drug-Amivantamab has been approved for the market and has emerged.
Due to the unique mechanism of action of Amivantamab and its excellent clinical efficacy in EGFR Exon20ins NSCLC, in May this year, the FDA accelerated the approval of Amivantamab for the treatment of EGFR that has progressed after platinum-based chemotherapy.
Patients with metastatic NSCLC with Exon20ins
.

This is the first drug approved by the FDA for this type of mutation
.

The Center for Drug Evaluation (CDE) of the National Medical Products Administration (NMPA) has also approved Amivantamab to be included in the breakthrough therapy program
.

Amivantamab will really benefit more patients with rare target mutations in NSCLC
.

The good clinical research performance of the drug is determined by its unique pharmacological mechanism of action
.

As a fully humanized EGFR-MET bispecific antibody, Amivantamab can be used to inhibit both EGFR and MET targets.
The mechanism of action mainly includes: 1) Inhibition of ligand binding: Amivantamab interacts with EGFR and c-MET in the cell The outer region binds to inhibit the ligand-receptor binding and the downstream signal transduction of the receptor; 2) Chemotactic activity of immune cells: promote tumors through NK cell-dependent ADCC effect and monocyte and macrophage-dependent ADCP effect Apoptosis; 3) Receptor degradation: Amivantamab binding triggers receptor degradation mediated by EGFR and c-MET receptors
.

The unique mechanism of action also indicates that Aminvantamab will be explored in more targeted therapies
.

The meeting also announced two new major developments in the CHRYSALIS study, two "firsts" respectively
.

One is the first to prove that Amivantamab has anti-tumor activity in patients with MET 14 exon skipping mutations; the second is the first to announce the efficacy and safety of Amivantamab combined with chemotherapy for the treatment of advanced NSCLC (including initial treatment/treatment and multiple EGFR mutation subtypes) Sex [5]
.

MET exon 14 skipping mutation research releases-Amivantamab has excellent performance prospects.
The CHRYSALIS study published on the WCLC [6] The results of the MET-2 cohort preliminarily showed that Amivantamab skipped mutations in MET 14 exon (METex14) The application in NSCLC is also promising
.

This cohort is currently enrolled in 19 patients with METex14 NSCLC who have received Amivantamab's RP2D treatment
.

The safety results showed that the safety of Amivantamab was consistent with previous reports.
16% of patients had ≥3 treatment-related adverse events (TRAE), mainly manifested as dyspnea, hypoproteinemia, and skin rash; 5% of patients stopped taking the drug.
11% of patients experienced dose reduction and 32% of patients experienced dose interruption.
The efficacy results showed that among the 19 patients with METex14 NSCLC treated with Amivantamab, 14 patients could be evaluated for efficacy, and 9 patients achieved partial remission (PR) ( ORR 64%, 9 people/14 people, 5 people have confirmed PR, 4 people are to be confirmed), the median time to the initial evaluation is 4.
1 months (range: 1.
6-9.
9), the median duration of treatment (DOT) It is 6.
5 months (range: 4.
3-12.
2)
.

Among them, among the 7 patients who had previously received anti-MET treatment, 4 patients received Amivantamab treatment and achieved PR
.

This result suggests that Amivantamab shows significant anti-tumor activity in METex14 NSCLC
.

This also confirmed that the bispecific targeting effect of Amivantamab showed therapeutic activity in both EGFR mutation and METex14 NSCLC patients
.

Figure 8 Amivantamab showed significant anti-tumor activity in METex14 NSCLC.
Amivantamab combined with chemotherapy-more EGFR mutation-positive NSCLC patients benefit.
Another cohort of the CRYSALIS study released at this conference, Amivantamab combined with chemotherapy is used to treat advanced NSCLC [7 ], the main purpose is to clarify the efficacy and safety of Amivantamab combined with chemotherapy for patients with advanced NSCLC
.

There are currently 20 patients enrolled in this cohort, of which 19 have EGFR positive mutations (19del 9 cases, 21 L858R 2 cases, 20ins 7 cases, 20 S768I 1 case), and 1 case has KRAS G13R mutation
.

Among them, 5 cases were newly treated patients, and 15 cases had received treatment in the past
.

The number of patients that can be used for efficacy evaluation is 18
.

Safety data show that the toxicity of Amivantamab combined with chemotherapy is consistent with the toxicity observed with a single treatment, and the overall patient can tolerate it
.

The most common TRAE is chemotherapy-induced neutropenia.
30% (n=6) of patients had serious treatment-related adverse events (AE), and most of the AEs were related to chemotherapy; dose reduction or drug withdrawal due to AE Six cases occurred, which were caused by diarrhea, nausea, upper gastrointestinal bleeding, cellulitis, hyponatremia, and changes in mental status (1 case each).
Most TRAEs were related to chemotherapy
.

Among them, diarrhea, nausea, and cellulitis are considered to be related to Amivantamab; the efficacy data of Amivantamab combined with chemotherapy in the study in Figure 9 shows that Amivantamab has anti-tumor activity in patients with different types of NSCLC
.

Among 18 patients who can be evaluated for efficacy, 8 patients were evaluated for efficacy as PR, and among 5 patients who were newly treated, 4 were evaluated for efficacy as PR
.

As of the date of publication, 12 of the 20 patients are still receiving treatment, with a median treatment time of 5.
6 months.
The cohort study is currently in progress; pharmacokinetics: chemotherapy does not affect the exposure of Amivantamab, and the exposure of Amivantamab It is similar under 28-day Q2W and 21-day Q3W dosing schedules
.

Figure 10 Anti-tumor activity of Amivantamab combined with chemotherapy At the same time, the PAPILLON Phase III study for evaluating the efficacy of Amivantamab combined with chemotherapy in the first-line treatment of EGFR Exon20ins is still ongoing
.

Finally, Professor Zhou Qing said that in the field of tumor treatment, with the continuous development of targeted therapy and immunotherapy in recent years, it is in line with traditional tumor treatment methods
.

The survival period of patients continues to prolong, and the quality of life is also significantly improved.
In the future, based on the good efficacy of Amivantamab as a new dual-antibody targeted drug for EGFR Exon20ins NSCLC patients, more explorations can be made about it and radiotherapy, chemotherapy, and other molecular targeted drugs and immunotherapy The feasibility, safety and effectiveness of the joint
.

These constructive research and explorations, if they can be transformed into clinically accessible application models in the future, will surely bring good news to more NSCLC patients and leave a strong mark in the history of NSCLC treatment in China
.

Expert profile Zhou Qing Professor of Oncology, PhD supervisor, Dean of Cancer Hospital, Guangdong Provincial People's Hospital, Deputy Director, Guangdong Lung Cancer Research Institute, Guangdong Provincial People's Hospital, Deputy Director, Guangdong Provincial Key Laboratory of Translational Lung Cancer Medicine, Guangdong Provincial People's Hospital, Cancer Center, Pulmonary Third Department Director, Chinese Society of Clinical Oncology (CSCO), Deputy Secretary-General, Chinese Thoracic Tumor Research Collaboration Group (CTONG), Vice-President and Secretary-General, Standing Committee, Chinese Medical Doctor Association, Oncology Multidisciplinary Diagnosis and Treatment Committee, Chairman, Guangdong Women Physicians Association, Lung Cancer Professional Committee, Guangdong Province Chairman of the Lung Cancer Special Committee of the Pharmaceutical Society Guangdong Provincial Medical Association Lung Oncology Branch Standing Committee Member of the First Committee of the Peasants and Workers Democratic Party Guangdong Provincial Committee Deputy Chairman of the General Branch of Guangdong Provincial People’s Hospital Latest Cancer Report" [2] Liquid Biopsy and Other Non-invasive Diagnostic Modalities.
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9/12/2021 *This article is only used to provide scientific information to medical professionals.
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