Takeda, Di Zhe, Zai Lab, and Yang Sen "compete on the same stage". Which EGFR exon20 inhibitor is better?

EGFR mutation is a common gene mutation in NSCLC patients, accounting for about 10% to 15%.
In Asian population, this value is about 40% to 50%
.

EGFR exon 20 insertion mutations account for approximately 9% of all EGFR-mutant NSCLCs

EGFR mutation is a common gene mutation in NSCLC patients, accounting for about 10% to 15%.

Mobocertinib (TAK-788)

Mobocertinib is a small molecule tyrosine kinase inhibitor (TKI) specifically designed to selectively inhibit epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor-2 (HER2) exon 20 mutations
.

It was granted breakthrough therapy designation by the FDA and CDE in April and October 2020, respectively, for the treatment of patients with EGFR Exon20 insertion mutation NSCLC who had disease progression during or after platinum-containing chemotherapy

The marketing application of mobocertinib is based on data from an open-label, multi-center phase I/II clinical trial (NCT02716116), 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

Source: ASCO 2021, the same below

The data deadline is November 1, 2020
.

In the PPP cohort (n=114), the ORR assessed by the IRC was 28%, the ORR assessed by the investigator was 35%, with 1 case of CR; the disease control rate (DCR) was 78%; the median duration of response (DOR) was 17.

In the EXCLAIM amplification cohort (n=96), the ORR assessed by IRC was 25%, with 1 CR; the DCR was 76%; the median DOR was not reached
.

The safety of Mobocertinib is controllable.
The most common treatment-related adverse events (TRAEs) include diarrhea (90%), rash (45%), paronychia (34%), nausea (32%), and decreased appetite (32%) , Dry skin (30%) and vomiting (30%)
.

TRAEs of grade 3 and above (≥5%) were diarrhea (21%)

DZD9008

DZD9008 is a targeted EGFR/HER2 exon 20 mutation inhibitor developed by Jiangsu Dizhe Pharmaceutical.
It was included in the breakthrough therapy by CDE on December 15, 2020.
The indication is to treat EGFR 20 carriers who have received at least one systemic chemotherapy in the past.
Locally advanced or metastatic NSCLC with exon insertion mutation
.

At the ASCO conference in 2021, the Phase I clinical data of DZD9008 for the treatment of NSCLC with EGFR exon 20 insertion mutation was disclosed for the first time in the form of an oral report at the metastatic NSCLC branch
.

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

Both studies (NCT03974022&CTR20192097) included dose escalation and expansion cohort

Between July 9, 2019 and February 5, 2021, 97 NSCLC patients with EGFR or HER2 mutations received DZD9008
.

The results show that the best tolerated dose (MTD) of DZD9008 is 400 mg

Fifty-six patients with more than 16 different EGFR exon20ins mutations received at least one treatment evaluation
.

Previous treatment status: median 2 (range 1-10), previous chemotherapy rate was 92.
9%; previous TKI rate treatment was 44.
6%, including 1 case of pozitinib; 42.
9% of patients had brain metastases
.

Partial remission was observed at dose levels ≥100 mg
.
Remission was observed in 2 patients who had previously received Amivantamab treatment
.
Anti-tumor activity was observed in different EGFR exon20ins mutant subtypes
.

The objective response rate of RP2D dose 300 mg once daily was 48.
4% (15/31), and the disease control rate (DCR) was 90.
3% (28/31)
.
As of the data cutoff date, the median duration of treatment was 100 days (range 1-422 days)
.
The longest duration of remission was more than 6 months, and 18 of 22 remission patients still had remission
.

All in all, DZD9008 has shown good safety characteristics and promising anti-tumor efficacy in EGFR exon20ins mutant NSCLC patients who have previously received treatment
.
Related Phase II studies are underway
.

CLN-081 (TAS6417)

CLN-081 is a new type of oral EGFR-TKI owned by Zai Lab.
It has a wide range of activities against EGFR mutations (including ins20), and its activity against wild-type EGFR in vitro is weaker than EGFR ins20, suggesting that CLN-081 may be more beneficial Clinical treatment window
.
At the ASCO annual meeting, CLN-081 disclosed the interim results of a Phase I/IIa dose escalation and expansion study for advanced EGFR ins20 NSCLC (NCT04036682)
.

In this adaptive trial, the Phase I dose escalation started with an accelerated titration (AT) design and was converted to a Rolling-Six design based on pre-specified safety standards or clinically active doses
.
Phase I cohort expansion occurs in any dose cohort where remission is observed
.
The transition from Phase I to Phase IIa is based on Simon's two-phase design
.

As of April 1, 2021, 45 patients have been treated with CLN-081, and 42 of them are evaluable
.
All patients had received at least first-line platinum-based system chemotherapy in the past
.
The proportions of patients who have received at least second-line therapy, immunotherapy, and EGFR-TKI therapy in the past were 73%, 56%, and 40%, respectively
.

In terms of safety, the incidence of all adverse events (AE) was 98%, and the incidence of grade 3 and above AEs was 44%
.
The incidence of treatment-related AE (TRAE) was 98%, and the incidence of TRAE of grade 3 and above was 18%
.
The most common TRAEs are rash (76%), diarrhea (22%), paronychia (22%), nausea (18%), stomatitis (18%), anemia (18%), elevated AST (16%) ) And dry skin (16%)
.
TRAE of grade 3 and above includes anemia (9%), elevated AST (4%), elevated ALP (4%), and diarrhea (2%)
.

There was 1 case of DLT (grade 3 diarrhea) at the 150 mg BID dose
.
Five patients (11%) required dose reduction, and 4 patients had dose reduction due to treatment-related AEs
.

In terms of efficacy, among 42 evaluable patients, 50% (21/42) observed partial remission (PR), of which 13 cases have been confirmed
.
At the 100 mg BID dose, 54% (7/13) of the patients achieved PR, of which 6 cases have been confirmed
.
The disease control rate at all dose levels was 64% (27/42)
.

All in all, CLN-081 has acceptable safety characteristics.
Compared with other EGFR inhibitors, the incidence and severity of diarrhea have been improved, and there is no need to prevent digestive system or skin-related toxicity
.
In the full dose range, in a variety of different EGFR ins20 variants, and in severely pretreated patients who have previously received EGFR-TKI (EGFR ins20 inhibitor) or checkpoint inhibitor treatment progress, CLN-081 showed impressive Encouraging anti-tumor activity
.
The extended dose for the phase 2 cohort was set at 100 mg BID
.

Amivantamab

On May 22, Amivantamab received accelerated approval from the FDA, becoming the first treatment for adult NSCLC with an insertion mutation in exon 20 of EGFR
.
The Phase 1 CHRYSALIS study data of the drug was announced during the WCLC2020 meeting (Abs#3031).
The ORR of Amivantamab in patients with EGFR Exon 20ins mutant NSCLC patients who failed platinum-based chemotherapy was 40%, and the median duration of remission was 11.
1 months
.
The median PFS was 8.
3 months, and the median overall survival (OS) was 22.
8 months
.
The clinical benefit rate (≥PR or SD≥11 weeks) was 74%
.

Source: WCLC2020

Considering that CHRYSALIS is a non-randomized, single-arm study, an external control (EC) can help explain the efficacy of amivantamab and understand the unmet needs in actual treatment
.
A study published on ASCO this year compared amivantamab with real-world therapy in patients with advanced NSCLC with Exon20ins who progressed after platinum-based chemotherapy
.

The CHRYSALIS study amivantamab efficacy analysis set included 81 patients, the external control (EC) analysis set included 174 patients, and the real world data came from 3 US companies (Flatiron, COTA, and ConcertAI)
.
The key inclusion criteria include: exon 20ins aNSCLC, previous platinum-based chemotherapy, ≥1 line after platinum-based treatment, and ECOG PS 0 or 1
.
Propensity score weighting is used to correct for differences in age, brain metastasis, ECOG PS, and the number of previous treatment lines (LOT)
.

The baseline demographics of the amivantamab and EC treatment groups are basically similar; compared with the EC, the amivantamab treatment group has a higher percentage of Asian patients (55.
6% vs.
13%), more lines of previous treatment, and a lower proportion of baseline brain metastases
.

The most commonly accepted treatments for external controls (EC) include non-platinum-based chemotherapy (25.
1%), immunotherapy (24.
2%), platinum-containing therapy (16.
3%), and EGFR-TKI (16.
3%)
.

The analysis showed that the median PFS of patients receiving amivantamab and EC treatment was 8.
3 months and 2.
9 months, respectively [HR = 0.
47 (95% CI, 0.
34, 0.
65)], and the median time to next treatment (TTNT) was 14.
8, respectively Months and 4.
8 months [HR = 0.
40 (95% CI, 0.
28, 0.
57)]; median OS was 22.
8 months and 12.
8 months, respectively [HR = 0.
49 (95% CI, 0.
31, 0.
77)]
.

The study suggested that for patients with EGFR Exon 20ins mutant NSCLC who failed platinum-based chemotherapy, Amivantamab showed an OS that was 10 months higher than the actual treatment
.
The poor performance of external controls, usually using immune checkpoint inhibitors, single-agent chemotherapy, and EGFR TKI therapy, highlights the ineffectiveness of these drugs and the urgent need to explore more mutation-specific therapies in advanced NSCLC
.