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(amivantamab-vmjw)

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RYBREVANT® (amivantamab-vmjw)

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Use of RYBREVANT in Metastatic NSCLC with Atypical or Uncommon EGFR Mutations

Last Updated: 01/13/2026

SUMMARY

  • RYBREVANT (amivantamab-vmjw) is a low fucose, fully human immunoglobulin G1 (IgG1)-based bispecific antibody with immune cell-directing activity that targets epidermal growth factor receptor (EGFR) mutations and mesenchymal-epithelial transition (MET) mutations and amplifications in non-small cell lung cancer (NSCLC).1
  • LAZCLUZE (lazertinib) is a third-generation EGFR tyrosine kinase inhibitor (TKI).2
  • CHRYSALIS-2 (NCT04077463) is an ongoing, phase 1/1b, open-label, multicenter, dose-escalation (phase 1) and dose-expansion (phase 1b) study evaluating the efficacy, safety, pharmacokinetics (PK), and immunogenicity of LAZCLUZE, as monotherapy and in combination with RYBREVANT in adult patients with metastatic or unresectable NSCLC harboring EGFR mutations (Exon 19 deletion [Exon19del] or Exon 21 L858R, Exon 20 insertion [Exon20ins], or uncommon EGFR mutations) with disease progression on previous standard of care (SOC) treatment.3
    • Tomasini et al (2025)4 reported the final results from CHRYSALIS-2 cohort C, which included patients with atypical EGFR mutations, excluding Exon19del, Exon 21 L585R, and Exon20ins mutations.
      • At a median follow-up of 16.1 months, among 105 efficacy-evaluable patients, the overall response rate (ORR) was 52% (95% confidence interval [CI], 42-62), the median overall survival (OS) was not estimable (NE, 95% CI, 22.8-NE), the median progression-free survival (PFS) was 11.1 months (95% CI, 7.8-17.8), the median duration of response (DOR) was 14.1 months (95% CI, 9.5-26.2), and the clinical benefit rate (CBR) was 79% (95% CI, 70-86; Table: CHRYSALIS-2 Cohort C: Investigator-Assessed Efficacy Outcomes).
      • The final safety profile for cohort C was consistent with previous reports for LAZCLUZE in combination with RYBREVANT. The most common grade ≥3 treatment-emergent adverse events (TEAEs) in patients receiving RYBREVANT in combination with LAZCLUZE were rash and hypoalbuminemia, reported in 14 (13%) and 8 (8%) patients, respectively (Table: CHRYSALIS-2 Cohort C: Summary of AEs).
      • In an exploratory analysis of patients treated with 1L RYBREVANT plus LAZCLUZE in CHRYSALIS-2 cohort C vs a real-world cohort of patients receiving physician-selected EGFR TKIs, the median overall survival (OS) was NE (95% CI, 26.3-NE) vs 19.6 months (95% CI, 5.6-52.7; hazard ratio [HR], 0.29 [95% CI, 0.12-0.71]; P=0.015), and the median time to treatment discontinuation (TTD) was 14 months (95% CI, 8.2-27.6) vs 3.7 months (95% CI, 1.6-17.1; HR, 0.44 [95% CI, 0.26-0.75]; P=0.008).5 
  • Wang et al (2023)6 conducted a real-world study that retrospectively evaluated the use of RYBREVANT with or without osimertinib and with or without concurrent radiation therapy in patients with EGFR-mutated (EGFRm) NSCLC (N=61). Seven patients had atypical EGFR mutations.
    • After a median treatment duration of 10.07 months among 7 evaluable patients with atypical mutations, 6 (85.7%) patients had a clinical response. The disease control rate (DCR) was 100% (Table: Atypical Mutations Cohort: Efficacy Outcomes).
    • Grade ≥3 AEs were reported in 3 (42.9%) patients and included rash (n=2, 28.6%) and pneumonitis (n=1, 14.3%). Grade 1/2 AEs included infusion-related reactions (IRR), rash, scalp rash, paronychia, fatigue, edema, and pneumonitis (Table: Atypical Mutations Cohort: Safety Outcomes).
  • Kim et al (2022)7 reported the case of a 67-year-old male with stage IV-B squamous cell lung carcinoma with osseous metastases and EGFR Exon 18 G719A mutation, treated with RYBREVANT alone.
    • After disease progression on osimertinib, chemotherapy, and immunotherapy, the patient started RYBREVANT monotherapy. RYBREVANT was tolerated well, reduced the size of parenchymal lesions, lung mass and lymphadenopathies, and reduced the fraction of the variant allele (G719A) from 25.6% at diagnosis to non-detectable post-RYBREVANT. The case demonstrated response in central nervous system (CNS; leptomeningeal) involvement.
  • Nagasaka et al (2021)8 reported preliminary experience with RYBREVANT in combination with chemotherapy (carboplatin and pemetrexed) from a cohort of the CHRYSALIS study (NCT02609776), an ongoing, phase 1, open-label, multicenter study in patients with advanced NSCLC (N=20). One patient had an EGFR Exon 20 S768I mutation and had received prior therapy (treatment not reported). This patient did not experience a reduction in target lesions as best change from baseline, though preliminary activity was observed across the heterogenous population. RYBREVANT in combination with chemotherapy had a toxicity profile consistent with that observed with each therapy alone; however, safety was not separately reported for this patient.

PRODUCT LABELING

clinical datA

CHRYSALIS-2 Study

Tomasini et al (2025)4 reported final results from CHRYSALIS-2 cohort C, which included patients with atypical EGFR mutations, excluding Exon19del, Exon 21 L585R, and Exon20ins mutations, who received LAZCLUZE in combination with RYBREVANT (n=105).

Study Design/Methods

  • Phase 1/1b, ongoing, open-label, multicenter study designed to evaluate the efficacy and safety of LAZCLUZE, at the recommended phase 2 dose (RP2D) in combination with RYBREVANT in adult patients with metastatic or unresectable NSCLC harboring atypical EGFR mutations.3 
  • Key eligibility criteria for cohort C4: atypical EGFR mutations, including but not limited to S768I, L861Q, and G719X; treatment-naïve or received ≤2 prior lines of treatment with chemotherapy and/or first- or second-generation EGFR TKI (afatinib; except those who received gefitinib, dacomitinib, erlotinib, or icotinib); ECOG PS 0-1; stable CNS metastases were allowed.
  • Patients received RYBREVANT plus LAZCLUZE in 28-day cycles until disease progression, unacceptable toxicity, noncompliance, withdrawal of consent, or discontinuation by investigator discretion.4
    • RYBREVANT 1050 mg (1400 mg if body weight [BW] ≥80 kg) was administered once weekly (QW) during cycle (C) 1, with the first infusion split over 2 days (350 mg on C1 Day [D] 1, and the remainder on C1D2), and then once every 2 weeks (Q2W) thereafter.
    • LAZCLUZE 240 mg orally (PO) was administered once daily.
  • Primary endpoint4: Investigator-assessed ORR per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1
  • Secondary endpoints4: DOR, PFS, CBR, OS, TTD, and safety (AEs)

Results

Patient Characteristics

CHRYSALIS-2 Cohort C: Demographics and Baseline Disease Characteristics4 
Characteristic
Overall Population (N=105)
Treatment-naïve Subgroup
(n=49)
Prior-treatment Subgroup
(n=56)
Median age, years (range)
64 (30-85)
60 (30-80)
67 (32-85)
Male, n (%)
53 (50)
27 (55)
26 (46)
Race, n (%)
   Asian
71 (68)
28 (57)
43 (77)
   White
31 (30)
19 (39)
12 (21)
   Black or African American
1 (1)
1 (2)
0
   Not reported
2 (2)
1 (2)
1 (2)
ECOG PS, n (%)
   0
33 (31)
18 (37)
15 (27)
   1
72 (69)
31 (63)
41 (73)
Prior therapies in metastatic setting, n (%)
   Treatment-naïve
49 (47)
49 (100)
0
   Prior afatinib
34 (32)
0
34 (61)
   Prior 1st-/2nd-generation EGFR
   TKI (other than afatinib)a
9 (9)
0
9 (16)
   Prior platinum chemotherapy
7 (7)
0
7 (13)
   Prior afatinib + prior platinum
   chemotherapy
6 (6)
0
6 (11)
Baseline brain metastasis, n (%)
33 (31)b
13 (27)
20 (36)
EGFR mutation,c n (%)
   Exon 18 G719Xd
59 (56)
27 (55)
32 (57)
   Exon 21 L861Xe
27 (26)
12 (24)
15 (27)
   Exon 20 S768Xf
24 (23)
13 (27)
11 (20)
   Exon 18 E709K
2 (2)
2 (4)
0
   Exon 18 E709A
2 (2)
1 (2)
1 (2)
   L833V
2 (2)
2 (4)
0
   R776C
2 (2)
2 (4)
0
   R776H
1 (1)
1 (2)
0
   R831H
1 (1)
1 (2)
0
   V744M
1 (1)
1 (2)
0
   V769L
1 (1)
0
1 (2)
   V774M
1 (1)
0
1 (2)
   Other
10 (10)
5 (10)
5 (9)
Note: Data cutoff date: January 12, 2024.
Abbreviations: ECOG PS, Eastern Cooperative Oncology Group performance status; EGFR, epidermal growth factor receptor; TKI, tyrosine kinase inhibitor.
a1st/2nd generation EGFR TKIs, other than afatinib, included gefitinib, dacomitinib, erlotinib, and icotinib.
bBrain metastasis was confirmed by imaging in 37 (35%) patients.
cPatients may be counted in more than one category. Overall, 29 (28%) patients had compound mutations.
dG719X included G719A, G719S, G719C. Compound mutations were observed in 24 patients in the overall population, with 14 in the treatment-naïve subgroup, and 10 patients in the prior-treatment subgroup.
eL861X included L861Q, L861R, and L861G. Compound mutations were observed in 7 patients in the overall population, with 4 patients in the treatment-naïve subgroup and 3 patients in the prior-treatment subgroup.
fS768X included S768I and S768L. Compound mutations were observed in 18 patients in the overall population, with 11 patients in the treatment-naïve subgroup and 7 patients in the prior-treatment subgroup.
Efficacy

CHRYSALIS-2 Cohort C: Investigator-Assessed Efficacy Outcomes4

Overall Cohort C
(N=105)
Treatment-naïve Subgroup
(n=49)
Prior-treatment Subgroup
(n=56)
Median follow-up, months (range)
16.1 (0.1-31.5)
17.3 (0.1-31.5)
15.4 (0.3-30.8)
ORR, % (95% CI)
52 (42-62)
57 (42-71)
48 (35-62)
   Median DOR, months (95% CI)
14.1 (9.5-26.2)
20.7 (9.9-NE)
11 (4.5-NE)
   DOR ≥6 months, n (%)a
38 (69)
21 (75)
17 (63)
Best response, n (%)
   CR
0
0
0
   PR
55 (52)
28 (57)
27 (48)
   SD
37 (35)
18 (37)
19 (34)
   PD
8 (8)
2 (4)
6 (11)
   NE/Unknown
5 (5)
1 (2)
4 (7)
CBR,b % (95% CI)
79 (70-86)
84 (70-93)
75 (62-86)
Median PFS, months (95% CI)
11.1 (7.8-17.8)
19.5 (11.2-NE)
7.8 (5.4-11.1)
Median OS, months (95% CI)
NE (22.8-NE)
NE (26.3-NE)
22.8 (16.9-NE)
   At 24-months, % (95% CI)
58 (43-70)
77 (56-89)
34 (12-58)
Abbreviations: CBR, clinical benefit rate; CI, confidence interval; CR, complete response; DOR, duration of response; NE, not estimable; ORR, overall response rate; OS, overall survival; PD, progressive disease; PFS, progression-free survival; PR, partial response; SD, stable disease.
aAmong responders.
bCBR is defined as the percentage of patients achieving confirmed CR, PR, or durable SD (duration of ≥11 weeks).
  • Exploratory biomarker analysis:
    • Most patients treated with 1L or later-line RYBREVANT plus LAZCLUZE in cohort C had solitary EGFR mutations.4
    • 1L RYBREVANT plus LAZCLUZE4:
      • Confirmed ORR for patients with solitary mutations vs compound mutations was 63% (95% CI, 44-79) vs 47% (95% CI, 23-72; nominal P=0.299).
    • Later-line RYBREVANT plus LAZCLUZE4:
      • Confirmed ORR for patients with solitary mutations vs compound mutations was 52% (95% CI, 37-67.5) vs 33% (95% CI, 10-65; nominal P=0.244).
    • Presence of solitary or compound EGFR mutations had no major impact on ORR. The endpoint was exploratory and not part of hierarchical hypothesis testing. This endpoint was not adjusted for multiple comparisons. Therefore, the P-values displayed are nominal, and statistical significance has not been established.4
    • Of the 73 patients with analyzable baseline circulating tumor DNA (ctDNA) data, 65 (89%) had detectable ctDNA, and 59 (81%) had any detectable pathogenic alterations. Among these patients, TP53 co-mutations were detected in 37 (63%) patients.4
      • ORR for patients with TP53 mutations vs without TP53 mutations was 54% (95% CI, 37-71) vs 46% (95% CI, 28-66).
    • P-loop and αC-helix compressing (PACC) mutations, classical-like mutations, and T790M-like mutations were observed in 38 patients, 14 patients, and 3 patients, respectively.4
      • ORR for patients with PACC mutations, classical-like mutations, and T790M-like mutations was 45% (95% CI, 29-62), 64% (95% CI, 35-87), and 67% (95% CI, 9-99), respectively.
        • Among patients with PACC mutations, the ORR in the treatment-naïve subgroup (n=16) and prior-treatment subgroup (n=22) was 38% and 50%, respectively.
        • Among patients with classical-like mutations, the ORR in the treatment-naïve subgroup (n=10) and prior-treatment subgroup (n=4) was 70% and 50%, respectively.
    • The presence of TP53 co-mutation and other pathogenic alterations was not associated with a lower response rate.4
Safety
  • The final safety profile for cohort C was consistent with previous reports for LAZCLUZE in combination with RYBREVANT (Tables: CHRYSALIS-2 Cohort C: Safety Summary and CHRYSALIS-2 Cohort C: Summary of TEAEs).4
  • The median duration of treatment was 11.1 months (range, 0.03-31.5) in the overall population, 12.7 months (range, 0.03-31.5) in the treatment-naïve subgroup, and 8.9 months (range, 0.2-29.9) in the previously treated subgroup.4
  • Grade ≥3 treatment-related AEs (TRAEs) were reported in 50 (48%) patients.4
    • The most common grade ≥3 TRAEs were rash (13%) and hypoalbuminemia (8%).
    • TRAEs leading to treatment discontinuation were reported in 7 (7%) patients.
    • Death occurred in 12 (11%) patients, of which 1 (1%) was considered related to treatment.
  • Venous thromboembolism (VTE) was reported in 31 (30%) patients.4
    • Most VTEs (71% [22/31]) occurred in the first 4 months of treatment.
    • Grade 3 VTEs were reported in 10 (10%) patients; no grade 4-5 events occurred.
    • At baseline, 16% (17/105) of all patients received anticoagulation for prophylaxis or based on medical history of VTE. Most patients (94% [29/31]) were not on anticoagulation at the time of first VTE.

CHRYSALIS-2 Cohort C: Safety Summary4 
TEAEs, n (%)
Cohort C (N=105)
Any TEAE
105 (100)
Grade ≥3 TEAE
73 (70)
Serious TEAEa
53 (50)
Dose interruption of any study agentb
73 (70)
Dose reduction of any study agent
52 (50)
Discontinuation of any study agent
29 (28)
Abbreviations: IRR, infusion-related reaction; TEAE, treatment-emergent adverse event.
aOf the patients with serious TEAEs, 22 (21%) were related to treatment.
bExcludes IRRs.

CHRYSALIS-2 Cohort C: Summary of TEAEs4
Most common (≥10% By Preferred Term) TEAES, n (%)
Cohort C (N=105)
All Grades
Grade ≥3
EGFR-related
   Rash
70 (67)
14 (13)
   Paronychia
70 (67)
5 (5)
   Stomatitis
31 (30)
2 (2)
   Diarrhea
24 (23)
0
   Pruritus
24 (23)
0
   Dermatitis acneiform
23 (22)
4 (4)
MET-related
   Hypoalbuminemia
62 (59)
8 (8)
   Peripheral edema
38 (36)
3 (3)
Other
   IRRsa
59 (56)
4 (4)
   ALT increased
43 (41)
2 (2)
   Constipation
34 (32)
0
   Hypocalcemia
33 (31)
1 (1)
   AST increased
32 (30)
1 (1)
   COVID-19
31 (30)
2 (2)
   Anemia
28 (27)
3 (3)
   Decreased appetite
28 (27)
2 (2)
   Nausea
27 (26)
2 (2)
   Asthenia
26 (25)
7 (7)
   Blood lactate dehydrogenase increased
24 (23)
7 (7)
   Hypokalemia
20 (19)
4 (4)
   Thrombocytopenia
19 (18)
2 (2)
   Muscle spasms
19 (18)
0
   Gamma-glutamyl transferase increased
18 (17)
1 (1)
   Cough
18 (17)
0
   Lymphopenia
17 (16)
2 (2)
   Fatigue
17 (16)
0
   Pulmonary embolism
16 (15)
8 (8)
   Peripheral sensory neuropathy
16 (15)
0
   Vomiting
16 (15)
0
   Pneumonia
15 (14)
10 (10)
   Dizziness
15 (14)
3 (3)
   Blood creatine phosphokinase increased
15 (14)
2 (2)
   Hypomagnesemia
15 (14)
0
   Hypophosphatasemia
15 (14)
0
   Myalgia
15 (14)
0
   Paresthesia
15 (14)
0
   Neutropenia
14 (13)
1 (1)
   Dry skin
14 (13)
0
   Hyponatremia
14 (13)
1 (1)
   Dyspnea
13 (12)
6 (6)
   Headache
13 (12)
0
   Pyrexia
13 (12)
0
   Blood creatinine increased
12 (11)
0
   Hyperglycemia
12 (11)
0
   Back pain
11 (11)
1 (1)
   Blood alkaline phosphatase increased
11 (11)
0
   Insomnia
11 (11)
0
   Leukopenia
11 (11)
0
Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; COVID-19 coronavirus disease 2019; EGFR, epidermal growth factor receptor; IRR, infusion-related reaction; MET, mesenchymal-epithelial transition; TEAE, treatment-emergent adverse event.
aMajority of IRRs (95%) occurred during the first infusion and were grade 1-2.

Trial Matched Real-world Analysis

Tomasini et al (2025)5 reported results from a real-world evidence (RWE) analysis that compared outcomes for 1L RYBREVANT plus LAZCLUZE from CHRYSALIS-2 cohort C vs 1L physician-selected EGFR TKI monotherapy from a matched real-world cohort of patients with atypical EGFRm advanced NSCLC.

Study Design/Methods

  • Prespecified, retrospective, observational, propensity-score weighted RWE analysis5
  • Patients in the real-world cohort were identified from the NSCLC Flatiron Health/Foundation Medicine Clinico-Genomic Database (FH/FMI CGDB) between January 01, 2014, and March 31, 2024.5
  • Subgroup analyses were performed with patients who received afatinib or osimertinib monotherapy.5
  • Key eligibility criteria5: atypical EGFR mutations, received first-line therapy, ECOG PS 0-1.

Results

Patient Characteristics
  • In the FH/FMI CGDB, 69 patients received 1L physician-selected EGFR TKIs, with osimertinib (49%) and afatinib (41%) being the most common.5
  • The most commonly observed atypical mutations in CHRYSALIS-2 cohort C treatment-naïve subgroup vs the real-world cohort were G719X (55% vs 57%), L861X (24% vs 38%), and S768X (27% vs 20%).5
  • Patient characteristics at baseline are summarized in Table: Real-world Cohort and CHRYSALIS-2 Cohort C: Demographics and Baseline Disease Characteristics.

Real-world Cohort and CHRYSALIS-2 Cohort C: Demographics and Baseline Disease Characteristics5
Characteristic
Real-world Cohorta
Cohort C Treatment-naïve Subgroup
(n=49)
Weighted P-Value
Weighted SMDb
Before ATT Weighting (n=69)
After ATT Weighting (n=46)
Mean age, years (SD)
71 (9.8)
60.2 (12.3)
60.4 (11)
0.971
0.012
ECOG PS, n (%)
   0
29 (42)
20 (44)
18 (37)
0.607
0.142
   1
40 (58)
26 (57)
31 (63)
History of brain metastasis, n (%)
25 (36)
16 (35)
13 (27)
0.508
0.184
History of smoking, n (%)
51 (74)
27 (59)
27 (55)
0.813
0.067
Mean time from advanced diagnosis to start of first LoT, months (SD)
10.7 (19.8)
4.7 (9.3)
4.7 (10.7)
0.982
0.004
Disease stage, n (%)c
   Nonadvanced (<IIIB)
15 (22)
4 (9)
5 (10)
0.928
0.018
   Advanced (≥IIIB)
51 (74)
38 (83)
44 (90)
Mean number of metastatic sites (SD)
1.8 (1.2)
2.3 (1.2)
2.4 (1.2)
0.691
0.106
Abbreviations: ATT, average treatment effect in the treated; ECOG PS, Eastern Cooperative Oncology Group performance status; LoT, line of therapy; SD, standard deviation; SMD, standardized mean difference.
aBaseline characteristics were well balanced between cohort C and the real-world cohort using propensity score weighting. ATT weights were applied to the real-world cohort to match cohort C.
bCalculated after weighting of the covariates.
cThere were 3 patients with missing disease stage data in the real-world cohort before weighting.
  • Real-world cohort attrition:
    • Of the 69 patients who received 1L EGFR TKI treatment, 41% died before receiving a subsequent line of therapy (LoT, median follow-up, 37.3 months), 6% received no subsequent LoT, 17% remained on 1L treatment, and 36% progressed to 2L treatment.5 The types of 2L treatment received are summarized in Table: Types of 2L Treatment.

Types of 2L Treatment5 
Type of 2L Treatmenta
n (%)
1L osimertinib, n
12
   EGFR TKI, n (%)
4 (33)
      Afatinib, n
3
      Osimertinib, n
1
   EGFR TKI + chemotherapy, n (%)
1 (8)
   Chemotherapy, n (%)
2 (17)
   Chemotherapy + I/O, n (%)
2 (17)
   I/O, n (%)
2 (17)
   RYBREVANT + osimertinib, n (%)
1 (8)
1L afatinib, n
10
   EGFR TKI: osimertinib, n (%)
6 (60)
   Chemotherapy + I/O, n (%)
1 (10)
   I/O, n (%)
3 (30)
Abbreviations: 1L, first-line; 2L, second-line; EGFR, epidermal growth factor receptor; I/O, immuno-oncology; TKI, tyrosine kinase inhibitor.
aPatients (n=3) who received erlotinib as 1L treatment were not included.
Efficacy
  • The median OS for 1L RYBREVANT plus LAZCLUZE in cohort C vs physician-selected EGFR TKIs was NE (95% CI, 26.3-NE) vs 19.6 months (95% CI, 5.6-52.7; HR, 0.29 [95% CI, 0.12-0.71]; P=0.015), respectively.5
    • The 24-month OS rate for RYBREVANT plus LAZCLUZE vs physician-selected EGFR TKIs was 77% vs 47%, respectively.
    • The 24-month OS rates for osimertinib and afatinib were 41% and 55%, respectively.
  • The median TTD for 1L RYBREVANT plus LAZCLUZE in cohort C vs physician-selected EGFR TKIs was 14 months (95% CI, 8.2-27.6) vs 3.7 months (95% CI, 1.6-17.1; HR, 0.44 [95% CI, 0.26-0.75]; P=0.008), respectively.5
    • The 24-month TTD rate for RYBREVANT plus LAZCLUZE vs physician-selected EGFR TKIs was 41% vs 10%, respectively.
    • The 24-month TTD rates for osimertinib and afatinib were 3% and 17%, respectively.

Real-world Retrospective Study

Wang et al (2023)6 conducted a real-world study that retrospectively evaluated the use of RYBREVANT with or without osimertinib and with or without concurrent radiation therapy in patients with EGFRm NSCLC (N=61). Seven patients had atypical EGFR mutations.

Results

Patient Characteristics

Atypical Mutations Cohort: Demographics and Baseline Disease Characteristics6
Characteristic
n=7
Median age, years (range)
69 (52–72)
Female, n (%)
4 (57.1)
Patients with never smoking history, n (%)
5 (71.4)
Median prior lines of therapy, n
4
Received ≥1 prior TKI, n (%)
7 (100)
Received RYBREVANT with osimertinib, n (%)
4 (57.1)
Received concomitant radiation, n (%)
4 (57.1)
Site of radiation, n
   Brain
2
   Bone
1
   Lung
0
   Other visceral sites
1
Abbreviation: TKI, tyrosine kinase inhibitor.
Efficacy

Atypical Mutations Cohort: Efficacy Outcomes6
Characteristic
n=7
Median time on treatment, months (range)
10.07 (1.13-13.8)
Clinical benefit, n (%)
   Clinical response
6 (85.7)
   Clinical stable
1 (14.3)
   Clinical progression
0 (0)
DCR, %
100
Abbreviations: DCR, disease control rate.
Safety
  • Grade ≥3 AEs were reported in 3 (42.9%) patients and included rash (n=2, 28.6%) and pneumonitis (n=1, 14.3%). Grade 1/2 AEs included IRR, rash, scalp rash, paronychia, fatigue, edema, and pneumonitis (Table: Atypical Mutations Cohort: Safety Outcomes).9

Atypical Mutations Cohort: Safety Outcomes9
AEs, n (%)
n=7
Grade 1/2
Grade ≥3
Overall
-
3 (42.9)
IRR
5 (71.4)
0 (0)
Rash
2 (28.6)
2 (28.6)
Scalp rash
2 (28.6)
-
Paronychia
3 (42.9)
-
Fatigue
1 (14.3)
-
Edema
1 (14.3)
-
Pneumonitis
-
1 (14.3)a
Abbreviations: AE, adverse event; IRR, infusion-related reaction.
aIncluding 1 death.

Case Study

Kim et al (2022)7 reported the case of a 67-year-old male with stage IV-B squamous cell lung carcinoma with osseous metastases and EGFR Exon 18 G719A mutation, treated with RYBREVANT alone.

  • Initially, the patient was started on osimertinib. After 2 months, he was hospitalized for drug-induced pneumonitis and osimertinib was discontinued. A chest computed tomography (CT) angiogram revealed disease progression.7
  • The patient was started on 2 cycles of chemotherapy followed by immunotherapy. After 10 weeks, a brain magnetic resonance imaging (MRI) revealed continued disease progression with new parenchymal and leptomeningeal metastases. Immunotherapy was discontinued and RYBREVANT monotherapy was initiated.7
  • The patient tolerated RYBREVANT well. He reported rash, which was managed with hydrocortisone cream. His performance status remained unchanged. After 6 weeks, repeat scans showed decreased leptomeningeal enhancement and reduced size of parenchymal lesions, lung mass, and lymphadenopathies. The ctDNA next generation sequencing (NGS) analysis revealed that variant allele (G719A) fraction had reduced from 25.6% at diagnosis to non-detectable levels post-RYBREVANT. The case demonstrated a response in CNS (leptomeningeal) involvement.7

Literature SearcH

A literature search of MEDLINE®, Embase®, BIOSIS Previews®, and Derwent Drug File (and/or other resources, including internal/external databases) was conducted on
17 November 2025.

 

References

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2 Cho BC, Felip E, Hayashi H, et al. MARIPOSA: phase 3 study of first-line amivantamab + lazertinib versus osimertinib in EGFR-mutant non-small-cell lung cancer. Future Oncol. 2022;18(6):639-647.  
3 Janssen Research & Development, LLC. An open-label phase 1/1b study to evaluate the safety and pharmacokinetics of JNJ-73841937 (lazertinib), a third generation EGFR-TKI, as monotherapy or in combinations with JNJ-61186372, a human bispecific EGFR and cMet antibody in participants with advanced non-small cell lung cancer. In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000- [cited 2025 November 17]. Available from: https://clinicaltrials.gov/study/NCT04077463 NLM Identifier: NCT04077463.  
4 Tomasini P, Wang Y, Li Y, et al. Amivantamab plus lazertinib in atypical EGFR-mutated advanced non-small cell lung cancer (NSCLC): results from CHRYSALIS-2. [published online ahead of print December 01, 2025]. J Clin Oncol. doi:10.1200/jco-24-02835.  
5 Tomasini P, Wang Y, Li Y. Supplement to: Amivantamab plus lazertinib in atypical EGFR-mutated advanced non-small cell lung cancer (NSCLC): results from CHRYSALIS-2. [published online ahead of print December 01, 2025]. J Clin Oncol. doi:10.1200/jco-24-02835.  
6 Wang K, Du R, Myall NJ, et al. Real-world efficacy and safety of amivantamab for EGFR-mutant NSCLC. J Thorac Oncol. 2024;19(3):500-506.  
7 Kim J, Choi H, Lee YH, et al. Response to amivantamab, a bispecific EGF and MET receptor directed antibody, in a patient with an atypical EGFR mutated (G719X) non-small cell lung cancer (NSCLC) with leptomeningeal disease who progressed on osimertinib [abstract]. Cancer Res. 2022;82(suppl 12):Abstract 4113.  
8 Nagasaka M, Goto K, Gomez J, et al. Amivantamab in combination with chemotherapy in patients with advanced non-small cell lung cancer (NSCLC). Poster presented at: International Association for the Study of Lung Cancer (IASLC) 2021 World Conference on Lung Cancer; September 8-14, 2021; Worldwide Virtual Event.  
9 Wang K, Du R, Myall NJ, et al. Supplement to: Real-world efficacy and safety of amivantamab for EGFR-mutant NSCLC. J Thorac Oncol. 2024;19(3):500-506.