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Amivantamab SC, RYBREVANT, LAZCLUZE - PALOMA-2 Study

Last Updated: 10/21/2024
  • RYBREVANT (amivantamab-vmjw) is a low fucose, fully human IgG1-based bispecific antibody with immune cell-directing activity that targets EGFR mutations and MET mutations and amplifications in NSCLC.1 Amivantamab for SC administration is an investigational coformulation with rHuPH20.2
  • LAZCLUZE (lazertinib) is a third-generation EGFR tyrosine kinase inhibitor.3

PALOMA-2 Study

  • PALOMA-2 (NCT05498428) is an ongoing, phase 2, open-label, international, parallel-cohort study evaluating the efficacy and safety of a SC formulation of amivantamab with chemotherapy and/or lazertinib combination therapy in patients with EGFR-mutated advanced NSCLC (N=520). The primary endpoint is investigator-assessed ORR.2,4
    • The interim efficacy, safety, and PK results of amivantamab SC plus lazertinib with prophylactic anticoagulation (cohort 1, n=68; cohort 6, n=58) in treatment-naïve patients with EGFR-mutated (Exon19del or Exon 21 L858R) advanced NSCLC are reported.2
      • At a median follow-up of 8.6 months, the investigator-assessed ORR was 75% (95% CI, 63-85) in cohort 1 and 80% (95% CI, 65-90) in cohort 6.
      • The most common TEAEs were associated with EGFR and MET inhibition and were primarily grade 1-2 in severity.
      • The ARR (MedDRA preferred term) rate was 15% in all patients.
      • The VTE rate was 18% in cohort 1 (recommended prophylactic anticoagulation) and 7% in cohort 6 (mandatory prophylactic anticoagulation).
      • TRAEs leading to discontinuation of all agents were reported in 9% of patients.
      • Mean (%CV) amivantamab coformulation trough concentrations on cycle 2 day 1 were 328 (32) µg/mL in cohort 1 and 373 (27) µg/mL in cohort 6.

Note: ARR, administration-related reaction; CI, confidence interval; CV, coefficient of variation; EGFR, epidermal growth factor receptor; Exon19del, Exon 19 deletion; IgG1, immunoglobulin G1; MedDRA, Medical Dictionary for Regulatory Activities; MET, mesenchymal-epithelial transition; NSCLC, non-small cell lung cancer; ORR, objective response rate; PK, pharmacokinetics; rHuPH20, recombinant human hyaluronidase PH20; SC, subcutaneous; TEAE, treatment-emergent adverse event; TRAE, treatment-related adverse event; VTE, venous thromboembolism.

Overview1

PALOMA-2 (NCT05498428) is an ongoing, phase 2, open-label, international, parallel-cohort study designed to assess the efficacy and safety of amivantamab SC with chemotherapy and/or lazertinib in patients with EGFR-mutated advanced NSCLC.

Eligibility Criteria2,4

Key Inclusion Criteria
  • Adults (age ≥18 years) with locally advanced or metastatic NSCLC
  • ≥1 measurable lesion per RECIST v1.1 (all cohorts except cohort 4)
  • ECOG PS 0 or 1
  • Brain metastases if present must be stable
  • Adequate organ functions

Study Design1,2

Efficacy Results2

Investigator- and ICR-Assessed ORR (Confirmed and Unconfirmed Responses)

Cohort 1
(n=68) 		Cohort 6
(n=45) 		Overall
(n=113)
INV ICR INV ICR INV ICR
ORR, % (95% CI) 75 (63- 85) 81 (70 -89) 80 (65 -90) 76 (61 -87) 77 (68 -84) 79 (70 -86)

Median follow-up was 10 months for cohort 1, 6.1 months for cohort 6, and 8.6 months overall

Safety Results2

  • The most common TEAEs were associated with EGFR and MET inhibition and were primarily grade 1-2 in severity.
  • ARRs were reported in 15% (19/125) of patients, with 90% of ARRs reported in cycle 1 (on or after cycle 1 day 1 but before the next dose).
  • Median time to ARR onset (defined as the start of ARR minus the start of the last injection prior to this event) was 2.3 hours (range, 0.3-7.2).
  • TRAEs leading to the discontinuation of all agents were reported in 9% (11/125) of patients.

PK2

  • Consistent with historic IV levels (mean [%CV], 317 [32] µg/mL from the MARIPOSA study), mean (%CV) amivantamab coformulation trough concentrations on cycle 2 day 1 were as follows:
  • Cohort 1 (n=50): 328 (32) µg/mL
  • Cohort 6 (n=42): 373 (27) µg/mL

Note: ARR, administration-related reaction; CI, confidence interval; CV, coefficient of variation; DOR, duration of response; ECOG PS, Eastern Cooperative Oncology Group performance status; EGFR, epidermal growth factor receptor; Exon19del, Exon 19 deletion; Exon20ins, Exon 20 insertion; ICR, independent central review; IV, intravenous; MET, mesenchymal- epithelial transition; NSCLC, non-small cell lung cancer; ORR, objective response rate; PK, pharmacokinetics; PO, orally; Q2W, every 2 weeks; Q3W, every 3 weeks; Q4W, every 4 weeks; QD, once daily; RECIST v1.1, Response Evaluation Criteria in Solid Tumors version 1.1; SC, subcutaneous; SC-CF, subcutaneous coformulation with recombinant human hyaluronidase PH20; TEAE, treatment-emergent adverse event; TRAE, treatment-related adverse event; TTR, time to response; US, United States; VTE, venous thromboembolism.

  • PALOMA-2 (NCT05498428) is an ongoing, phase 2, open-label, international, parallel-cohort study designed to assess the efficacy and safety of amivantamab SC with chemotherapy and/or lazertinib in patients with EGFR-mutated advanced NSCLC. 2,4
  • Amivantamab SC, coformulated with rHuPH20, is administered by manual injection in the abdomen.2,4

PALOMA-2 (ClinicalTrials.gov Identifier: NCT05498428); data cutoff date: January 6, 2024.
aReceived first-line regimen.
b1600 mg (2240 mg if BW ≥80 kg) QW for the first 4 weeks then Q2W for cohorts 1 and 6; 28-day cycle.
c1600 mg (2240 mg if BW ≥80 kg) on C1D1, then 2400 mg (3360 mg if BW ≥80 kg); 21-day cycle.
dExperienced disease progression on or after osimertinib treatment.
e1050 mg (1400 mg if BW ≥80 kg).
f3520 mg (4640 mg if BW ≥80 kg); 28-day cycle.
gExperienced disease progression on or after amivantamab plus lazertinib.
hAll cohorts except cohort 4; primary endpoint for cohort 4: safety.
iAll cohorts except cohort 4; secondary endpoint for cohort 4: PRO.

  • Interim efficacy, safety, and PK results were reported for amivantamab SC plus lazertinib with the prophylactic anticoagulation either recommended (cohort 1) or mandatory (cohort 6) in treatment-naïve patients with EGFR-mutated (Exon19del or Exon 21 L858R) advanced NSCLC.2
  • In total, 126 patients received amivantamab SC plus lazertinib in cohort 1 (n=68) and cohort 6 (n=58).2

Demographics and Baseline Disease Characteristics2

Characteristic Characteristic Cohort 1
(n=68) 		Cohort 6
(n=58) 		Total
(n=126)
Median age, years (range) 58 (28-85) 62 (34-83) 59 (28-85)
Female, n(%) 42 (62) 34 (59) 76 (60)
Race, n (%)
Asian 45 (66) 40 (69) 85 (67)
White 19 (28) 16 (28) 35 (28)
Othera 4 (6) 2 (3) 6 (5)
ECOG PS 1, n (%) 48 (71) 43 (75) 91 (72)
History of smoking, n (%) 15 (22) 18 (31) 33 (26)
History of brain metastases, n (%) 20 (29) 18 (31) 38 (30)
EGFR mutation,b n (%)
Exon19del 45 (66) 34 (59) 79 (63)
Exon 21 L858R 24 (35) 24 (41) 48 (38)
Adenocarcinoma subtype, n (%) 65 (96) 57 (98) 122 (97)

aIncludes Black or African American and American Indian/Alaska Native.
bPatients could be included in >1 category.

Primary Endpoint2

  • At a median follow-up of 8.6 months, the investigator-assessed ORR with amivantamab SC plus lazertinib was 77% (95% CI, 68-84) for both cohorts 1 and 6.
    • In cohort 1 (median follow-up, 10 months; n=68) and cohort 6 (median follow-up, 6.1 months; n=45), the investigator-assessed ORR was 75% (95% CI, 63-85) and 80% (95% CI, 65-90), respectively.

Secondary Endpoints2

  • The ICR-assessed ORR reported with amivantamab SC plus lazertinib was comparable with previous reports of RYBREVANT IV plus lazertinib.
    • The overall ICR-assessed ORR was 79% (95% CI, 70-86; cohort 1, 81% [95% CI, 70-89]; cohort 6, 76% [95% CI, 61-87]).
  • The investigator-assessed best responses, TTR, and DOR in confirmed responders were evaluated across cohorts 1 and 6.

Investigator-Assessed Best Response, TTR, and DOR2

Parameters Confirmed Responders
(n=111)
Best responses,a n
CR 0
PR 75
SD 33
PD 2
Median TTR, months (range) 1.9 (1.4-5.3)
Median DOR,a,b months NE

aPatients without postbaseline tumor assessment were excluded.
bn=75.

  • AEs reported with amivantamab SC plus lazertinib were consistent with previous reports of RYBREVANT IV plus lazertinib. The most common TEAEs (≥20%) were associated with EGFR and MET inhibition and were primarily grade 1-2 in severity.2
  • ARRs were reported in 15% (19/125) of patients.2
    • ARRs (90%; 18/20) were mostly reported in cycle 1 (on or after cycle 1 day 1 but before the next dose).
    • One patient reported 2 ARRs (1 on cycle 1 day 1 and 1 on cycle 1 day 9).
    • Median time to ARR onset (defined as the start of ARR minus the start of the last injection prior to this event) was 2.3 hours (range, 0.3-7.2).
  • TRAEs leading to discontinuation of all agents were reported in 9% (11/125) of patients.2
  • In the safety-evaluable set, 48 (71%) patients in cohort 1 and 57 (100%) patients in cohort 6 received prophylactic anticoagulation (apixaban, rivaroxaban, dalteparin, or enoxaparin as included in the national treatment guidelines; please refer to individual product labels for complete Prescribing Information).2
  • VTE was reported in 13% (16/125) of all patients, with 18% (12/68) in cohort 1 and 7% (4/57) in cohort 6.2
    • Most VTEs were grade 1-2 in severity; no grade 5 events were reported.
    • No VTEs led to dose reductions.
  • Of the 12 patients in the prophylactic anticoagulation group who reported VTE, 11 (92%) reported VTE after receiving prophylactic anticoagulation.2
    • Median onset time of VTE after discontinuing prophylactic anticoagulation was 70 days (range, 2-185).

VTE and Bleeding Events Based on Prophylactic Anticoagulation Use2

n (%) Any Prophylactic
Anticoagulation
(n=105) 		No Prophylactic
Anticoagulation
(n=20) 		Total
(n=125)
Any VTEa 12 (11) 4 (20) 16 (13)
Grade ≥3 0 1 (5) 1 (1)
Grade 5 0 0 0
Any VTE leading to death 0 0 0
Any VTE leading to any discontinuation 0 0 0
Grade ≥3 bleedingb 2 (2)c 0 2 (2)

aVTE AEs were identified using the SMQ for “Embolic and Thrombotic events, Venous (SMQ),” and the preferred term was “Thrombosis” or “Embolism.”
bBleeding AE terms were identified using the SMQ for “Hemorrhage Terms (Excl Laboratory Terms)” (narrow scope).
cOne patient had been on rivaroxaban 10 mg PO daily since day 1 and developed chronic pigmented purpura on day 67, which resolved on day 79; another patient had been on rivaroxaban 10 mg PO daily since day 1 and developed grade 3 subarachnoid hemorrhage on day 76, which remained unresolved.

  • Consistent with historic IV levels (mean [%CV], 317 [32] µg/mL from the MARIPOSA study), mean (% CV) amivantamab coformulation trough concentrations on cycle 2 day 1 were as follows2:
    • Cohort 1 (n=50): 328 (32) µg/mL
    • Cohort 6 (n=42): 373 (27) µg/mL
AE Adverse event OS Overall Survival
ALT Alanine aminotransferase PD Progressive Disease
ARR Administration-related reaction PFS Progression-free survival
AST Aspartate aminotransferase PK Pharmacokinetics
BW Body Weight PO Orally
CBR Clinical benefit rate PR Partial response
C1D1 Cycle 1 day 1 PRO Patient-reported outcome
CI Confidence interval Q2W Every 2 weeks
CR Complete response Q3W Every 3 weeks
CV Coefficient of variation Q4W Every 4 weeks
DOR Duration of response QD Once daily
ECOG PS Eastern Cooperative Oncology Group performance status QW Once a week
EGFR Epidermal growth factor receptor RECIST v1.1 Response Evaluation Criteria in Solid Tumors version 1.1
Exon19del Exon 19 deletion rHuPH20 Recombinant human hyaluronidase PH20
Exon20ins Exon 20 insertion SC Subcutaneous
ICR Independent central review SC-CF Subcutaneous coformulation with recombinant human hyaluronidase PH20
IgG1 Immunoglobulin G1 SD Stable disease
IV Intravenous SMQ Standardized MedDRA query
MedDRA Medical Dictionary for Regulatory Activities TEAE Treatment-emergent adverse event
MET Mesenchymal-epithelial transition TRAE Treatment-related adverse event
NE Not estimable TTR Time to response
NSCLC Non-small cell lung cancer US United States
ORR Objective response rate VTE Venous thromboembolism

A literature search of MEDLINE®, Embase®, BIOSIS Previews®, and Derwent Drug File (and/or other resources, including internal/external databases) was conducted on 03 June 2024.

  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. Lim SM, Tan JL, Dias JM, et al. Subcutaneous amivantamab and lazertinib as first-line treatment in patients with EGFR- mutated advanced non-small cell lung cancer (NSCLC): interim results from the phase 2 PALOMA-2 study. Poster presentation at: American Society of Clinical Oncology (ASCO) Annual Meeting; May 31-June 4, 2024; Chicago, IL.
  3. 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.
  4. Janssen Research & Development, LLC. A phase 2, open-label, parallel cohort study of subcutaneous amivantamab in multiple regimens in patients with advanced or metastatic solid tumors including EGFR-mutated non-small cell lung cancer. In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000- [cited 2024 June 3]. Available from: https://clinicaltrials.gov/study/NCT05498428 NLM Identifier: NCT05498428.