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

Last Updated: 08/20/2024

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 lazertinib, a novel oral third-generation EGFR TKI, as monotherapy and in combination with RYBREVANT in adult patients with metastatic or unresectable NSCLC harboring EGFR mutations (Exon 19 deletion [Exon19del] or L858R, Exon 20 insertion [Exon20ins], or uncommon EGFR mutations) with disease progression on previous standard of care (SOC) treatment.3
    • Cho et al (2021)4 reported initial results from CHRYSALIS-2 cohort C, which included patients with atypical EGFR mutations excluding Exon20ins, who received lazertinib in combination with RYBREVANT (n=52).
    • Cho et al (2024)5 reported final results from CHRYSALIS-2 cohort C.
      • At a median follow-up of 16.1 months among 105 efficacy-evaluable patients, the ORR was 52% (95% CI, 42-62), the median progression-free survival (PFS) was 11.1 months (95% CI, 7.8-17.8), the median DOR was 14.1 months (95% CI, 9.5-26.2), and the CBR was 79% (95% CI, 70-86) (Table: CHRYSALIS-2 Cohort C: Investigator-Assessed Outcomes).
      • The final safety profile for cohort C was consistent with previous reports for lazertinib in combination with RYBREVANT. The most common grade ≥3 adverse event (AE) was rash, reported in 14 (13%) patients receiving lazertinib in combination with RYBREVANT (Table: CHRYSALIS-2 Cohort C: Summary of AEs).
  • 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

Cho et al (2021)4 reported initial results from CHRYSALIS-2 cohort C, which included patients with atypical EGFR mutations excluding Exon20ins mutations, who received lazertinib in combination with RYBREVANT (n=52).

Study Design/Methods

  • Phase 1/1b, ongoing, open-label study designed to confirm the safety of lazertinib, an oral third‑generation EGFR TKI, at the recommended phase 2 dose (RP2D) and evaluated the efficacy, safety, and PK of lazertinib in combination with RYBREVANT in adult patients with metastatic or unresectable NSCLC harboring EGFR mutations who have had disease progression with previous SOC treatment.
  • Key eligibility criteria for cohort C: atypical EGFR mutations excluding Exon20ins; treatment-naïve or prior first- or second-generation EGFR TKI (afatinib; except those who received osimertinib).
  • Primary endpoint: ORR
  • Secondary endpoints: DOR, PFS, CBR (defined as partial response [PR]/complete response [CR] or stable disease [SD] with a duration of ≥11 weeks), overall survival (OS), and safety (AEs)

Results

Patient Characteristics

CHRYSALIS-2 Cohort C: Interim Demographics and Baseline Disease Characteristics4
Characteristic, n (%)
n=52a
Median age, years (range)
64 (30-85)
Male/Female
28 (54)/24 (46)
Race
   Asian
35 (67)
   White
10 (19)
   Not reported
7 (14)
ECOG PS
   0
17 (33)
   1
35 (67)
Types of prior therapy
   Any prior afatinib
19 (37)
   Any prior platinum-based chemotherapy
9 (17)
   Any prior other EGFR TKI
4 (8)
   Treatment-naïve
26 (50)
   Other
10 (19)
Baseline brain metastases
13 (25)
EGFR mutationb
   Exon 18 G719X
27 (52)
   Exon 21 L861Q
14 (27)
   Exon 20 S768I
8 (15)
   L833V
2 (4)
   L861R
2 (4)
   Exon 18 E709K
2 (4)
   V744M
1 (2)
   Otherc
5 (10)
Abbreviations: ECOG PS, Eastern Cooperative Oncology Group performance status; EGFR, epidermal growth factor receptor; TKI, tyrosine kinase inhibitor.
aPatients who received ≥1 dose of the study intervention.
bThere were numerous cases of multiple or compound mutations.
cIncludes E709_T710delinsD, EGFR p.E709_T710delinsD (Exon 18), p.E709_T710delinsD, activated mutation of Exon 19 C.2217_2234dup and RAD51 fusion, and rearrangement of intron 26.

Efficacy
  • At the time of the clinical cutoff (May 31, 2022), a total of 30 patients were efficacy-evaluable, and the ORR was 53% (95% CI, 34-72).
  • Among 40 patients who were response-evaluable (patients who received ≥1 dose of the study drug and had ≥1 scheduled post-baseline disease assessment or discontinued treatment for any reason), PRs were observed in individuals with Exon 20 S768I, Exon 21 L861Q, Exon 18 E709K, G719X, L861R, and other EGFR mutations.
    • Responses were observed in tumors characterized by multiple mutations.
  • Among patients who received prior afatinib or other EGFR TKI treatment (n=16), 15 patients were EGFR T790M negative, and 1 patient was T790M positive by central circulating tumor DNA (ctDNA) testing.
  • Two patients (prior afatinib, n=1; treatment-naïve, n=1) had MET amplification.
  • Of the 40 response-evaluable patients, 31 (78%) remained on treatment at the time of the clinical cutoff.
    • The median duration of treatment among 21 responders was 5.95 months (range, 2.3-11.8+).

CHRYSALIS-2 Cohort C: Summary of Interim Efficacy Outcomes4
Prior Afatinib
Treatment-Naïve
All Evaluable
Efficacy-evaluable patients,a n
6
17
30
   ORR, % (95% CI)
50 (12-88)
59 (33-82)
53 (34-72)
Response-evaluable patients,b n
16
21
40
   ≥30% reduction in tumor lesions, n (%)
8 (50)
15 (71)c
-
   CBR, % (95% CI)
69 (39-91)
81 (58-95)
78 (62-89)
   Median DOR (range)
-
-
NE (2.86-NE)d
Abbreviations: CBR, clinical benefit rate; CI, confidence interval; DOR, duration of response; NE, not evaluable; ORR, overall response rate; PR, partial response.
a
Patients who received ≥1 dose of the study drug and had ≥3 scheduled post-baseline disease assessments or discontinued treatment for any reason.
bPatients who received ≥1 dose of the study drug and had ≥1 scheduled post-baseline disease assessment or discontinued treatment for any reason.
cConfirmed PRs, n=12; pending confirmation, n=3.
dAmong the 10 patients with a treatment duration of ≥6 months, 4 patients had a DOR of ≥6 months.

Safety
  • The safety profile of RYBREVANT was consistent with previous reports for lazertinib in combination with RYBREVANT.
  • AEs of special interest included rash, venous thromboembolism (VTE), and interstitial lung disease (ILD).
    • Rash-related AEs (cumulative grouped) were observed in 39 (75%) patients, of which 7 were grade 3.
    • VTEs were reported in 14 patients, of which 4 were grade ≥3.
    • Grade 1 ILD was reported in 2 patients.
  • Treatment-related dose reductions for RYBREVANT and lazertinib occurred in 8 (15%) and 10 (19%) patients, respectively.
  • Treatment-emergent AEs (TEAEs) of either or both drugs leading to treatment discontinuation were reported in 3 (6%) patients.

CHRYSALIS-2 Cohort C: Summary of Interim TEAEs4
TEAEs (≥15%), n (%)
n=52
EGFR-related
   Rash
27 (52)
   Paronychia
18 (35)
   Stomatitis
14 (27)
   Diarrhea
10 (19)
   Pruritis
10 (19)
   Dermatitis acneiform
8 (15)
MET-related
   Hypoalbuminemia
24 (46)
   Peripheral edema
13 (25)
Other
   IRR
27 (52)
   Nausea
14 (27)
   Constipation
14 (27)
   Increased ALT
14 (27)
   Decreased appetite
13 (25)
   Hypocalcemia
11 (21)
   Asthenia
11 (21)
   Increased AST
11 (21)
   Hypokalemia
10 (19)
   Anemia
10 (19)
   Thrombocytopenia
9 (17)
   Increased blood LDH
9 (17)
   Fatigue
9 (17)
   Pulmonary embolism
8 (15)
   Lymphopenia
8 (15)
Abbreviations: ALT, alanine transaminase; AST, aspartate transaminase; EGFR, epidermal growth factor receptor; LDH, lactate dehydrogenase; MET, mesenchymal-epithelial transition; IRR, infusion-related reaction; TEAE, treatment-emergent adverse event.
aPatients who received ≥1 dose of the study intervention (safety population).

Cho et al (2024)5 reported final results from CHRYSALIS-2 cohort C (n=105).

Results

Patient Characteristics

CHRYSALIS-2 Cohort C: Demographics and Baseline Disease Characteristics5
Characteristic
Cohort C (n=105)
Median age, years (range)
64 (30-85)
Male/female, n (%)
53 (50)/52 (50)
Race, n (%)
   Asian
71 (68)
   White
31 (30)
   Black or African American
1 (1)
   Not reported
2 (2)
ECOG PS, n (%)
   0
33 (31)
   1
72 (69)
Prior therapies in metastatic setting, n (%)
   Treatment-naïve
49 (47)
   Prior afatinib
34 (32)
   Prior 1st-/2nd-generation EGFR TKI (other than afatinib)a
9 (9)
   Prior platinum chemotherapy
7 (7)
   Prior afatinib + prior platinum chemotherapy
6 (6)
Baseline brain metastasis, n (%)
33 (31)
EGFR mutation,b n (%)
   Exon 18 G719X
60 (57)c
   Exon 21 L861X
27 (26)d
   Exon 20 S768X
25 (24)e
   Exon 18 E709K
2 (2)
   Exon 20 E709A
2 (2)
   L833V
2 (2)
   R776C
2 (2)
   R776H
1 (1)
   R831H
1 (1)
   V744M
1 (1)
   V769L
1 (1)
   V774M
1 (1)
   Other
10 (10)
Abbreviations: ECOG PS, Eastern Cooperative Oncology Group performance status; EGFR, epidermal growth factor receptor; TKI, tyrosine kinase inhibitor.
a
1st/2nd generation EGFR TKIs other than afatinib included gefitinib, dacomitinib, erlotinib, and icotinib.
bPatients may be counted in more than one category.
cG719X included G719A, G719S, G719C.
dL861X included L861Q, L861R, and L861G.
eS768X included S768I and S768L.

Efficacy
  • First-line RYBREVANT plus lazertinib:
    • The presence of TP53 co-mutation and other pathogenic alterations was not associated with a lower response rate.
  • Second- or third-line RYBREVANT plus lazertinib:
    • 88% of patients received a prior EGFR TKI.
    • The presence of TP53 co-mutation and other pathogenic alterations was not associated with a lower response rate.

CHRYSALIS-2 Cohort C: Investigator-Assessed Outcomes5
Overall Cohort C (n=105)
1st-Line RYBREVANT + Lazertinib (n=49)
2nd-/3rd-Line RYBREVANT + Lazertinib (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
NA
NA
   PR
55 (52)
NA
NA
   SD
37 (35)
NA
NA
   PD
8 (8)
NA
NA
   NE/UNK
5 (5)
NA
NA
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)
Abbreviations: CBR, clinical benefit rate; CI, confidence interval; CR, complete response; DOR, duration of response; NA, not available; NE, not estimable; ORR, overall response rate; OS, overall survival; PD, progressive disease; PFS, progression-free survival; PR, partial response; SD, stable disease; UNK, unknown.
a
Among responders.
b
CBR is defined as the percentage of patients achieving confirmed CR or PR, or durable SD (duration of ≥11 weeks).

  • Real-world efficacy:
    • The median OS and median TTD for 49 patients treated with first-line RYBREVANT plus lazertinib in cohort C was NE (95% CI, 27.7 months-NE) and 14 months (95% CI, 9.7-NE), respectively. Real-world data from the Flatiron Health/Foundation Medicine Clinico-Genomic Database showed that the median OS and median TTD for 83 patients with advanced NSCLC with atypical EGFR mutations and ECOG PS 0-1 who received first-line treatment was 17.2 months (95% CI, 13.6-31.6) and 3.2 months (95% CI, 2.3-4.8), respectively.
Safety
  • The final safety profile for cohort C was consistent with previous reports for lazertinib in combination with RYBREVANT.
  • 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.

CHRYSALIS-2 Cohort C: Summary of AEs5
AEs (≥20%) By Preferred Term, n (%)
Cohort C (n=105)
All Grades
Grade ≥3
EGFR-related
   Rash
70 (67)
14 (13)
   Paronychia
70 (67)
5 (5)
   Dermatitis acneiform
23 (22)
4 (4)
MET-related
   Hypoalbuminemia
62 (59)
8 (8)
   Peripheral edema
38 (36)
3 (3)
Other
   Infusion-related reactions
59 (56)
4 (4)
   Alanine transaminase increased
43 (41)
2 (2)
   Constipation
34 (32)
0
   Hypocalcemia
33 (31)
1 (1)
   Aspartate transaminase increased
32 (30)
1 (1)
   COVID-19
31 (30)
2 (2)
   Stomatitis
31 (30)
2 (2)
   Anemia
28 (27)
3 (3)
   Decreased appetite
28 (27)
2 (2)
   Nausea
27 (26)
1 (1)
   Asthenia
26 (25)
7 (7)
   Pruritus
24 (23)
0
   Diarrhea
24 (23)
0
   Blood lactate dehydrogenase increased
24 (23)
0
Abbreviations: AE, adverse event; COVID-19 coronavirus disease 2019; EGFR, epidermal growth factor receptor; MET, mesenchymal-epithelial transition.

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 Characteristics4
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 Outcomes4
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; TKI, tyrosine kinase inhibitor.
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.
  • 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.
  • 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.

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
30 May 2024.

References

1 Moores SL, Chiu ML, Bushey BS, et al. A novel bispecific antibody targeting EGFR and cMet is effective against EGFR inhibitor-resistant lung tumors. Cancer Res. 2016;76(13):3942-3953.  
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 2024 June 11]. Available from: https://clinicaltrials.gov/ct2/show/NCT04077463 NLM Identifier: NCT04077463.  
4 Cho BC, Wang Y, Li Y, et al. Amivantamab in combination with lazertinib in patients with atypical epidermal growth factor receptor (EGFR) mutations excluding exon 20 insertion mutations: initial results from CHRYSALIS-2. Oral presentation presented at: European Society for Medical Oncology (ESMO) Congress; December 3, 2022; Singapore.  
5 Cho BC, Wang Y, Felip E, et al. Amivantamab plus lazertinib in atypical EGFR-mutated advanced non-small cell lung cancer (NSCLC): results from CHRYSALIS-2. Oral Presentation presented at: American Society of Clinical Oncology (ASCO) Annual Meeting; May 31-June 4, 2024; Chicago, IL.  
6 Wang K, Du R, Myall NJ, et al. Real-world efficacy and safety of amivantamab for EGFR-mutant non-small cell lung cancer (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 Research. 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 for: Real-world efficacy and safety of amivantamab for EGFR-mutant non-small cell lung cancer (NSCLC). J Thorac Oncol. 2024;19(3):500-506.