Comparison of EGFR Exon20 inhibitors: Johnson & Johnson Amivantamab vs Takeda Mobocertinib

On July 12, the marketing authorization application (NDA) of the innovative drug Mobocertinib (TAK-788), which was certified by China and the United States for breakthrough therapy, was officially accepted by the Center for Drug Evaluation (CDE) of the National Medical Products Administration (NMPA) and was approved It is included in the priority review and approval procedure and is intended to be used for the treatment of adult patients with non-small cell lung cancer (NSCLC) carrying epidermal growth factor receptor (EGFR) exon 20 insertion mutations
.

Mobocertinib's US NDA was also granted priority review by the FDA in April this year, and it may achieve simultaneous approval in China and the world
.

However, for the EGFR exon20 mutation, Amivantamab has taken the lead and obtained accelerated approval from the FDA on May 21 for the treatment of locally advanced or metastatic adult NSCLC patients who have undergone or have undergone platinum-containing chemotherapy and have progressed after receiving platinum-containing chemotherapy

Epidemiological data

Epidemiological data

In 2004, the epidermal growth factor receptor (EGFR) mutation was identified as a driving gene for the clinical progress of non-small cell lung cancer (NSCLC)
.

In East Asia, about 40% of lung cancer patients carry EGFR mutations.

Source: Reference 1

Drug discovery

Drug discovery

Amivantamab is an EGFR/MET specific dual-antibody drug, and its discovery process will not be involved in this article
.

Here, only a brief overview of the discovery process of the small molecule drug Mobocertinib

Source: Reference 2

Clinical research data

Clinical research data

Study Design The accelerated approval of Amivantamab is based on a multi-center, open multi-cohort phase I clinical study (CHRYSALIS, NCT02609776)
.

In the CHRYSALIS study, patients with EGFR exon 20 insertion mutation confirmed by testing received intravenous injection according to their body weight

CHRYSALIS study design (source WCLC2020) The marketing application of mobocertinib is based on data from an open-label, multi-center phase I/II clinical trial (NCT02716116)
.

The study includes dose escalation, dose expansion, and EXCLAIM expansion cohorts.

Mobocertinib research design (Source: ASCO2021)

It is not difficult to see from the clinical design that there are different administration methods due to different types of drugs
.

Amivantamab is administered intravenously based on the patient's weight, while Mobocertinib is administered orally

CHRYSALIS study patient baseline data (Source: WCLC 2020)

In the EXCLAIM cohort, the median age of patients was younger than that of the CHRYSALIS study
.

The proportion of women and Asians is higher than that of the CHRYSALIS study; in addition, the proportion of patients with an ECOG score of 1, no smoking history, and brain metastases is also higher than that of the CHRYSALIS study

Mobocertinib study patient baseline (source: ASCO2021)

Effectiveness The final effectiveness data shows that patients receiving Amivantamab treatment have an ORR of 40%, of which the CR rate is 3.
7% and the PR rate is 36%
.

The clinical benefit rate was 74%, the median DoR was 11.

CHRYSALIS effectiveness data (source WCLC2020)

CHRYSALIS effectiveness data (source FDA instructions)

The efficacy data of Mobocertinib (EXCLAIM cohort) showed that the confirmed ORR was 25% and all were PR
.
The median DoR has not been reached, and the confirmed DCR is 76% (DCR is defined as CR, PR, or the best response to stable disease after starting the study drug for at least 6 weeks)
.

Mobocertinib validity data (source: ASCO2021)

In terms of safety and safety, the most common adverse reactions (≥20%) of Amivantamab treatment include skin rash, infusion-related reactions, paronychia, musculoskeletal pain, dyspnea, nausea, edema, cough, fatigue, stomatitis, constipation, vomiting and Itching
.
The most common abnormal indicators (≥2%) for grade 3-4 detection include decreased lymphocytes, decreased phosphate, decreased albumin, increased glucose, increased γ-glutamyltransferase, decreased sodium and potassium, and increased alkaline phosphatase
.

Amivantamab safety data (source: FDA instructions)

The most common adverse events (≥20%) associated with Mobocertinib treatment include diarrhea, rash, paronychia, decreased appetite, dry skin, nausea, increased creatinine, stomatitis, vomiting, acnoid dermatitis, pruritus, and increased amylase
.

Mobocertinib security data (source: ASCO2021)

Among them, the common serious adverse events ≥3 grade (≥2%) were diarrhea, nausea, increased creatinine and stomatitis
.

Mobocertinib security data (source: ASCO2021)

Compared with Amivantamab (35%), patients treated with Mobocertinib had a higher proportion of grade 3 adverse events
.
66% of patients had grade ≥3 adverse events, the proportion of treatment-related adverse events ≥ grade 3 was 42%, and the proportion of serious AEs was 44%
.
One patient died of heart failure related to Mobocertinib treatment
.

Guide recommendation

Guide recommendation

In the fifth edition of the NCCN Guidelines (NSCLC) in 2021, Amivantamab was added as a second-line treatment for patients with EGFR exon insertion mutations
.
Currently, Mobocertinib has not been included in the NCCN guidelines recommendation
.

A picture summary

A picture summary

Reference materials:

1.
Vyse and Huang.
Targeting EGFR exon 20insertion mutations in NSCLC.
Signal Transduction and Targeted Therapy (2019)4:5

2.
Gonzalvez et al.
Cancer Discov2021;11:1–16

3.
Amivantamab source: FDA website; WCLC2020 (Sabari JK et al.
Phase 1 CHRYSALIS Study in Exon20ins NSCLC #3031)

4.
Mobocertinib data source: ASCO2021: #9014; WCLC2020 (Caicun Zhou: Mobocertinib in NSCLC With EGFR Exon 20 Insertions: Results FromEXCLAIM and Platinum-Pretreated Patient Populations)