The FDA ( U.S. Food and Drug Administration ) has granted the accelerated approval of Rybrevant ( Amivantamab-vmjw; Amivantamab ) for the treatment of adult patients with locally advanced or metastatic non-small cell lung cancer ( NSCLC ) with epidermal growth factor receptor ( EGFR ) exon 20 insertion mutations, as detected by an FDA-approved test, whose disease has progressed on or after Platinum-based chemotherapy.
Rybrevant is the first fully-human, bispecific antibody approved for the treatment of patients with NSCLC that targets EGFR exon 20 insertion mutations, which are the third most prevalent activating EGFR mutation.
This indication is approved under accelerated approval based on overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.
Amivantamab is a fully-human bispecific antibody directed against EGFR and MET receptors.
It binds extracellularly inhibiting tumor growth and leading to tumor cell death.
Accelerated FDA approval is based on positive results from the phase 1 CHRYSALIS study, a multicenter, open-label, clinical study evaluating Rybrevant as a monotherapy in patients enrolled in the prior Platinum containing chemotherapy cohort.
The FDA simultaneously approved Guardant Health’s Guardant360 CDx liquid biopsy blood test as a companion diagnostic for use with Rybrevant.
Next-generation sequencing tests offer an alternative to polymerase chain reaction ( PCR )-based tests which fail to identify 50% or more of exon 20 insertion mutations.
. CHRYSALIS is a phase 1 open-label, multicenter, first-in-human study to evaluate the safety, pharmacokinetics and preliminary efficacy of Amivantamab as a monotherapy and in combinations including with Lazertinib, a novel third-generation EGFR TKI, in adults with advanced NSCLC.
The study consists of two parts: Amivantamab monotherapy and combination-dose escalations and Amivantamab monotherapy and combination-dose expansions.
In the ongoing phase 1 CHRYSALIS study, patients with locally advanced or metastatic NSCLC with EGFR Exon 20 insertion mutations weighing less than 80 kg received Amivantamab 1050 mg and patients weighing at least 80 kg or more received Amivantamab 1400 mg weekly for four weeks, with the initial dose as a split infusion in week 1 on day 1 and day 2, then administered every two weeks thereafter until disease progression or unacceptable toxicity.
Disease response using overall response rate ( ORR ), per RECIST v1.1 as evaluated by Blinded Independent Central Review ( BICR ), was the primary endpoint.
In the prior-Platinum chemotherapy treated cohort ( n=81 ), the confirmed ORR, as assessed by blinded independent central review, was 40% ( 95% CI, 29-51 ), with 3.7% having complete responses ( CR ) and 36% achieving partial responses ( PR ).
Permanent discontinuation of Rybrevant due to an adverse reaction occurred in 11% of patients who received Rybrevant.
Adverse effects resulting in permanent discontinuation of Rybrevant in greater than or equal to 1% of patients were pneumonia, infusion-related reactions ( IRR ), pneumonitis / interstitial lung disease ( ILD ) dyspnea, pleural effusion and rash.
Dose interruptions of Rybrevant due to adverse effects occurred in 78% of patients.
IRR requiring infusions interruptions occurred in 59% of patients.
Adverse reactions requiring dose interruption in greater than or equal to 5% of patients included dyspnea, nausea, rash, vomiting, fatigue and diarrhea.
The most common adverse effects ( greater than or equal to 20% ) in patients who received Rybrevant were rash ( 84% ), IRR ( 64% ), paronychia ( 50% ), musculoskeletal pain ( 47% ), dyspnea ( 37% ), nausea ( 36% ), fatigue ( 33% ), edema ( 27% ), stomatitis ( 26% ), cough ( 25% ), constipation ( 23% ) and vomiting ( 22% ).
Worldwide, lung cancer is one of the most common cancers, and NSCLC makes up 80 to 85% of all lung cancers.
The main subtypes of NSCLC are adenocarcinoma, squamous cell carcinoma and large cell carcinoma.
Among the most common driver mutations in NSCLC are alterations in EGFR, which is a receptor tyrosine kinase supporting cell growth and division. EGFR mutations are present in 10 to 15% of people with NSCLC adenocarcinoma and occur in 40 to 50% of Asians.
The five-year survival rate for all people with metastatic NSCLC and EGFR mutations treated with EGFR TKIs is less than 20%.
EGFR exon 20 insertion mutations are the third most prevalent activating EGFR mutation.
Patients with EGFR exon 20 insertion mutations have a real-world five-year overall survival of 8% in the frontline setting, which is worse than patients with EGFR exon 19 deletions or L858R mutations, who have a real-world five-year overall survival of 19%. ( Xagena )
Source: Janssen, 2021