2021 ASCO targets lung cancer EGFR ex20ins, new drugs compete

ASCO series: 2021 ASCO LBA is launched-involving five major cancer types, Chinese research is selected for the first time | 2021 ASCO is about to open, the five frontiers of breast cancer are warming up EGFR (epidermal growth factor receptor) mutations are non-small cell lung cancer (NSCLC) Common genetic mutations in patients account for about 10% to 15%.
In Asian populations, this value is about 40% to 50%
.

EGFR exon 20 insertion mutations (EGFR ex20ins) account for about 4%-12% of all EGFR mutations.
Due to the variable structure and low tumor mutation burden, these patients are usually insensitive to EGFR-TKIs and immunotherapy, and their prognosis Poor, has always been regarded as a difficult clinical problem
.

What is gratifying is that this ASCO conference announced a number of research advances for EGFR ex20ins mutant NSCLC.
The specific efficacy is shown below! 1.
Mobocertinib (TAK-788) (Abstract No.
9014) Mobocertinib is a small molecule tyrosine kinase inhibitor (TKI) designed to selectively target EGFR and HER2 ex20ins
.

In April 2020, the US FDA granted Mobocertinib a breakthrough therapy designation for the treatment of NSCLC patients with EGFR ex20ins mutations that have progressed after receiving platinum-based chemotherapy
.

Mobocertinib's marketing application is based on an open-label, multi-center phase I/II clinical trial data, including dose escalation, dose extension, and EXCLAIM expansion cohort
.

This time ASCO disclosed the updated results of 114 platinum pretreatment (PPP) cohorts and EXCLAIM amplification cohorts in the trial
.

As of November 1, 2020, the results showed that the platinum pretreatment cohort (n=114) received Mobocertinib for a median treatment time of 7 months, and the ORR (Objective Response Rate) confirmed by the IRC (Independent Review Committee) was 28% The ORR estimated by the investigator was 35%; the disease control rate (DCR) was 78%; the median PFS (progression-free survival) was 7.
3 months; and the median overall survival (OS) was 24 months
.

Subgroup analysis showed that regardless of whether the patients received EGFR-TKI therapy, immunotherapy, or different EGFR exon 20ins mutation subtypes, the therapeutic benefit of Mobocertinib was observed
.

EXCLAIM expansion cohort (n=96): The median treatment time for receiving Mobocertinib was 6.
5 months, the ORR assessed by IRC was 25%, the ORR assessed by the investigator was 32%, the DCR was 76%, and the PFS was 7.
3 months, medium The bit OS has not yet arrived
.

The safety of Mobocertinib is controllable, and the most common treatment-related adverse events (TRAEs) include diarrhea, rash, paronychia, and nausea
.

2.
DZD9008 (abstract number: 9008) DZD9008 is a global innovative small molecule inhibitor for EGFR/HER2 ex20ins mutation independently developed by China.
The first indication is NSCLC with EGFR ex20ins mutation
.

Preclinical studies have shown that DZD9008 has significant inhibitory activity on EGFR/HER2 ex20ins mutant tumors, and at the same time has weak inhibitory effect on wild-type EGFR, so it has good selectivity
.

At this ASCO meeting, the Phase I clinical data of DZD9008 for the treatment of EGFR ex20ins mutant NSCLC was disclosed for the first time
.

The study aims to evaluate the safety, tolerability, pharmacokinetics and preliminary anti-tumor efficacy of DZD9008 in patients with EGFR or HER2 mutant NSCLC
.

Both studies (NCT03974022 and CTR20192097) included dose escalation and expansion cohorts
.

A pooled analysis was used to determine the recommended dose (RP2D) for the Phase II study
.

From July 2019 to February 2021, a total of 97 NSCLC patients with EGFR or HER2 mutations were enrolled and received DZD9008 administration
.

The results showed that the best tolerated dose (MTD) of DZD9008 was 400 mg, and the dose-limiting toxicities (DLTs) were diarrhea and arrhythmia
.

Fifty-six patients (42.
9% of patients with brain metastases) underwent the efficacy evaluation
.

Partial remission was observed at dose levels ≥100 mg
.

The RP2D dose was 300 mg/d, the ORR was 48.
4%, and the DCR was 90.
3%
.

Anti-tumor activity was observed in different EGFR ex20ins mutant NSCLC subtypes
.

As of the data cutoff date, the average treatment time was 100 days (range 1-422)
.

The longest remission lasted more than 6 months, and 18 of 22 remission patients were still responding
.

3.
Amivantamab (abstract number: 9502) Amivantamab is an EGFR/c-Met double antibody drug.
It has been approved by the FDA as the first drug for EGFR ex20ins mutant NSCLC
.

At the 2020 ASCO conference, the results of the Phase I CHRYSALIS study were announced
.

Data show that in patients with advanced NSCLC with EGFR ex20ins mutations, Amivantamab treatment showed durable remission: among all evaluable patients, ORR was 36%, median DOR was 10 months, and clinical benefit rate (≥ partial remission [ PR] + stable disease ≥ 12 weeks) was 67%; among evaluable patients who had previously received platinum-containing chemotherapy, the ORR was 41%, the median DOR was 7 months, and the clinical benefit rate was 72%
.

The study announced at this year's ASCO meeting aimed to evaluate the treatment of Amivantamab and real-world treatments in patients with advanced NSCLC who have advanced EGFR ex20ins after platinum-based chemotherapy
.

A total of 81 patients were included in the study.
The results showed that the median PFS of patients treated with Amivantamab and external controls (including chemotherapy, immunotherapy, and EGFR-TKI) were 8.
3 months and 2.
9 months, respectively [HR = 0.
47 (95% CI, 0.
34, 0.
65)], the median time to receive next treatment (TTNT) were 14.
8 months and 4.
8 months, respectively [HR = 0.
40 (95% CI, 0.
28, 0.
57)]; median OS were 22.
8 months and 12.
8, respectively Months [HR = 0.
49 (95% CI, 0.
31, 0.
77)]
.

For patients with EGFR ex20ins mutant NSCLC patients who failed platinum chemotherapy, Amivantamab showed higher OS and was well tolerated
.

4.
CLN-081 (TAS6417) (abstract number: 9077) CLN-081 is a new type of oral EGFR-TKI with wide adaptability for EGFR mutations
.

This year's ASCO annual meeting announced the interim results of a multi-center Phase I/IIa trial to evaluate the role of CLN-081 in advanced EGFR ex20ins mutant NSCLC
.

As of April 1, 2021, the study included 45 patients with EGFR ex20ins mutant NSCLC who had previously been treated with platinum drugs
.

The enrolled patients received CLN-081 treatment with doses of 30 mg, 45 mg, 65 mg, 100 mg, and 150 mg, respectively
.

Among the 42 patients with evaluable efficacy, 98% achieved the best response with partial remission or stable disease.
Among them, 21 achieved PR, 20 patients had SD, and 1 disease progressed
.

≥6 months DCR reaches 64%
.

Of the patients receiving 100mg BID, 54% (7/13) of the patients achieved PR
.

CLN-081 took effect quickly, and 76% of patients showed some degree of tumor shrinkage in the sixth week of treatment
.

The patient's reported dyspnea, shortness of breath, and coughing symptoms improved rapidly
.

5.
Poziotinib (abstract number: 9093) NSCLC patients with EGFR ex20ins mutations generally have a higher risk of brain metastasis
.

Poziotinib is a small molecule targeted drug with high brain-into-cerebral activity
.

The ASCO conference announced a phase II clinical trial of poziotinib, the ZENITH20 study, focusing on the treatment of EGFR ex20ins mutant NSCLC with brain metastases
.

The study was divided into three cohorts: the first cohort (n=115) had patients with EGFR gene mutation and had been treated with anti-EGFR drugs; the second cohort (n=90) had patients with HER2 gene mutation and had been treated with anti-HER2; Three cohorts (n=79) had EGFR gene mutations but were not treated
.

All three groups of patients included patients with stable brain metastases
.

The enrolled patients took 16 mg of poziotinib orally every day, and the follow-up time was up to 24 months
.

The results showed that the treatment response rate for patients with brain metastases was 22.
2%, and the disease control rate was 88.
9%
.

The proportion of patients in the three groups with stable disease was 80.
6%, and the patients in the second group had no disease progression
.

This indicates that poziotinib has a therapeutic effect on EGFR and HER2 insertion mutations, and it also has therapeutic activity on patients with brain metastases
.

More targeted drugs targeting exon 20 mutations of the EGFR gene are in clinical trials
.

Although this type of gene mutation is relatively rare, its proportion is still not a minority relative to the base number of lung cancer patients in China
.

We all hope that patients will have more and more medication options
.

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