Amivantamab Demonstrates 40% Overall Response Rate in EGFR Exon 20 Insertion-Mutant NSCLC Patients in Phase I CHRYSALIS Trial

January 29, 2021/BioonBIOON/-- Janssen Pharmaceuticals, a subsidiary of Johnson & Johnson (JNJ), recently participated in the virtual 21st World Conference on Lung Cancer (WCLC) hosted by the International Association for the Study of Lung Cancer in 2020.MeetingNew data from the Phase I CHRYSALIS study (NCT02609776) of amivantamab, an EGFR-MET bispecific antibody, for the treatment of lung cancer were published. The study was conducted in patients with metastatic or unresectable non-small cell lung cancer (NSCLC) harboring EGFR exon 20 insertion mutations who experienced disease progression during or after platinum-based chemotherapy. Currently, there are no approved targeted therapies for this patient population.

The results showed that amivantamab has potent clinical anti-TumorActive and durable response:The overall response rate (ORR) was 40%, the median duration of response (DOR) was 11 months, the median progression-free survival (PFS) was 8.3 months, the median overall survival (OS) was 22.8 months, and the clinical benefit rate (defined as disease status ≥ partial response or stable disease ≥ 11 weeks) was 74%.These data have been submitted to the United States.FDAand the EU EMA, representing a significant step toward addressing the high unmet needs in this patient population.

Dr. Joshua K. Sabari, conference presenter and a physician at NYU Langone’s Perlmutter Cancer Center, stated: “For patients with non-small cell lung cancer (NSCLC) harboring EGFR exon 20 insertion mutations, the disease typically responds poorly to chemotherapy and tyrosine kinase inhibitors used to treat other epidermal growth factor receptor (EGFR) mutations; therefore, there is a critical need for new treatment options. The CHRYSALIS study results presented today demonstrate that amivantamab has the potential to address this key unmet need and provide significant clinical benefits to patients.”

Globally, lung cancer is the most common type of cancer, with non-small cell lung cancer (NSCLC) accounting for 80–85% of all lung cancer cases. The main subtypes of NSCLC are adenocarcinoma, squamous cell carcinoma, and large cell carcinoma. The most common driver mutations in NSCLC are alterations in the EGFR gene, which encodes a receptor tyrosine kinase that facilitates cell growth and division. EGFR mutations are present in 10–15% of NSCLC patients and in 40–50% of Asian NSCLC patients with adenocarcinoma. EGFR exon 20 insertion mutations represent a distinct subset of lung adenocarcinoma, accounting for at least 9% of all EGFR mutations. Currently, the 5-year survival rate for patients with metastatic NSCLC is only 6%.

NSCLC patients with EGFR exon 20 insertion mutations are typically insensitive to approved EGFR tyrosine kinase inhibitors (TKIs) and have a poorer prognosis compared to patients with more common EGFR mutations (exon 19 deletions/L858R substitutions). Currently, the estimated median overall survival (OS) for lung cancer patients with EGFR exon 20 insertion mutations is 16 months. The standard of care is conventional cytotoxic chemotherapy, as there are no approved targeted therapies available.

Amivantamab is an investigational fully human EGFR–mesenchymal-epithelial transition factor (MET) bispecific antibody with immune cell-directed activity, targeting activating and resistant EGFR and MET mutations and amplifications.Tumor。The production and development of amivantamab adhere to the licensing agreement signed between Janssen Biotech, Inc. and Genmab for the use of the DuoBody technology platform.

Based on the overall response rate and durability of response data from the CHRYSALIS study, in December 2020, Janssen Pharmaceuticals submitted marketing authorization applications for amivantamab to the U.S. FDA and the European EMA for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) who have progressed after platinum-based chemotherapy and harbor exon 20 insertion mutations in the epidermal growth factor receptor (EGFR) gene. In March 2020, the United StatesFDAAmivantamab was granted Breakthrough Therapy Designation (BTD).

Notably, this marks the first regulatory submission in the EU and US for the treatment of patients with NSCLC harboring EGFR exon 20 insertion mutations. If approved,Amivantamab will become the first therapy specifically targeting NSCLC with EGFR exon 20 insertion mutations.

Mechanism of Action of Amivantamab (Image source: literature—doi-10.1158/2159-8290.CD-20-0116)

CHRYSALIS, a first-in-human, open-label, multicenter Phase I study, is evaluating the safety, pharmacokinetics, and efficacy of amivantamab as monotherapy and in combination with lazertinib, a novel third-generation EGFR-TKI, in adult patients with advanced NSCLC.

In the analysis presented at this conference, researchers evaluated the efficacy and safety of amivantamab in patients with non-small cell lung cancer (NSCLC) harboring EGFR exon 20 insertion mutations who had experienced disease progression after prior platinum-based chemotherapy (the post-platinum cohort). In the study, patients in this cohort received amivantamab at the recommended Phase 2 dose (RP2D: 1050 mg, or 1400 mg for patients weighing ≥80 kg). The primary endpoint was the overall response rate (ORR), with disease response assessed according to the Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1). Other endpoints included duration of response (DOR), clinical benefit rate, progression-free survival (PFS), and overall survival (OS).

The results showed that in the post-platinum efficacy cohort (n=81), the objective response rate (ORR) assessed by blinded independent central review (BICR) was 40% (n=32, 95% CI: 29–51), with 3 patients (4%) achieving complete response (CR) and 29 patients (36%) achieving partial response (PR). Among patients who achieved a response, the responses were durable, with a median duration of response (DOR) of 11.1 months (95% CI: 6.9–not reached [NE]). Twenty patients (63%) maintained a response for ≥6 months. The median progression-free survival (PFS) was 8.3 months (95% CI: 6.5–10.9), and the median overall survival (OS) was 22.8 months (95% CI: 14.6–not reached [NE]). The clinical benefit rate (≥PR or stable disease for ≥11 weeks) was 74% (95% CI: 63–83).

Among patients receiving amivantamab at the RP2D (n=114), the most common treatment-emergent adverse events (TEAEs) were rash (86%), infusion-related reactions (IRR, 66%), and paronychia (45%). Other adverse events included stomatitis (21%) and pruritus (17%). Grade ≥3 adverse events were reported in 35% of patients, with 16% considered treatment-related; the most common were rash (4%) and IRR (3%). No treatment-related deaths were reported. Treatment-related adverse events leading to dose reduction and discontinuation occurred in 13% and 4% of patients, respectively.. (Bioon.com)

Original Source: New Amivantamab Data from CHRYSALIS Study Show Robust Clinical Activity and Durable Responses in Patients with Metastatic or Unresectable Non-Small Cell Lung Cancer and EGFR Exon 20 Insertion Mutations