Dosage and Administration - Dosing Synchronization with Chemotherapy for Dose Delays in PAPILLON and MARIPOSA-2 Studies

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
• PAPILLON (NCT04538664) is an ongoing, phase 3, randomized, open-label study designed to compare the efficacy and safety of RYBREVANT plus chemotherapy (carboplatin and pemetrexed; n=153) vs chemotherapy alone (carboplatin and pemetrexed; n=155) in patients with untreated locally advanced or metastatic NSCLC and EGFR exon 20 insertion (Exon20ins) mutations.^3,4
  • The guidance for RYBREVANT dosing synchronization with chemotherapy in the event of a delay in RYBREVANT and/or chemotherapy dose in the RYBREVANT-chemotherapy arm is summarized below and in the Figure: PAPILLON: Dosing Synchronization for RYBREVANT-Chemotherapy Arm.⁵
• MARIPOSA-2 (NCT04988295) is an ongoing, phase 3, randomized, open-label study designed to assess the efficacy and safety of RYBREVANT-LAZCLUZE-chemotherapy (pemetrexed and carboplatin; n=263) and RYBREVANT-chemotherapy (pemetrexed and carboplatin; n=131) vs chemotherapy alone (pemetrexed and carboplatin; n=263) in patients with EGFR-mutated (Exon 19 deletion [Exon19del] or Exon 21 L858R substitution) locally advanced or metastatic NSCLC on or after osimertinib monotherapy.^6,7
  • The guidance for RYBREVANT dosing synchronization with chemotherapy in the event of a delay in RYBREVANT and/or chemotherapy dose in the RYBREVANT-LAZCLUZE-chemotherapy and RYBREVANT-chemotherapy arms is summarized below.⁸
• Please refer to RYBREVANT product labeling for complete safety information, including dose modification guidelines for adverse reactions.
• Please refer to product labeling for carboplatin and/or pemetrexed for complete prescribing information.

CLINICAL DATA

PAPILLON Study

Study Design/Methods

• Phase 3, ongoing, randomized, open-label study designed to compare the efficacy and safety of RYBREVANT plus chemotherapy (carboplatin and pemetrexed; n=153) vs chemotherapy alone (carboplatin and pemetrexed; n=155) in patients with untreated locally advanced or metastatic NSCLC and EGFR Exon20ins mutations.^3,4
  • RYBREVANT 1400 mg intravenous (IV; 1750 mg IV for baseline body weight ≥80 kg) was administered every week for the first 4 weeks, with the initial dose as a split infusion on Cycle 1 Day 1 (C1D1) and Day 2 (C1D2), followed by RYBREVANT 1750 mg IV (2100 mg IV for body weight ≥80 kg) every 3 weeks starting at week 7 Cycle 3 Day 1 until disease progression.
  • Pemetrexed 500 mg/m² IVwas administered every 3 weeks until disease progression.⁵
  • Carboplatin area under the curve (AUC) 5 IV was administered every 3 weeks for up to 4 cycles.

The information below summarizes interventions investigators in the PAPILLON study were instructed to perform to manage RYBREVANT and/or chemotherapy dose delays.

Dose Delay Guidance

• When treatment delay was indicated, the chemotherapy and/or RYBREVANT dose could be delayed until recovery of toxicity to a level allowing continuation of treatment. A patient for whom treatment was delayed was to be assessed at least weekly to ensure adequate supportive care was being administered and to assess for improvement of toxicity.⁵
• Prior to restarting treatment, patients must have met retreatment criteria for chemotherapy and/or RYBREVANT in accordance with the product labeling, study protocol, and local guidelines.⁵

Combination Chemotherapy (Pemetrexed with or without Carboplatin)

• If retreatment criteria were not met for carboplatin and/or pemetrexed, then retreatment was delayed by 1 week at a time.⁵
• If chemotherapy could not be administered on the scheduled day, dosing with RYBREVANT was continued as planned, if retreatment criteria were met.⁵
• If chemotherapy was delayed by 1 week (eg, administered on Day 8 of the cycle), then the subsequent cycle dosing of RYBREVANT could also be delayed by 1 week to align with the chemotherapy dosing schedule. Alternatively, if chemotherapy was delayed twice (eg, administered on Day 15 of the cycle), then the subsequent cycle dosing of RYBREVANT could be accelerated by 1 week to align with chemotherapy (Figure: PAPILLON: Dosing Synchronization for RYBREVANT-Chemotherapy Arm).⁵
• While some flexibility in the RYBREVANT dosing schedule was allowed (as described above), combination chemotherapy had to be dosed at a minimum interval of 21 days (carboplatin administration could not exceed a total of 4 cycles).⁵
• If chemotherapy administration was delayed beyond 42 days (±3 days) from the last treatment, then chemotherapy was discontinued unless approved by the sponsor.⁵

RYBREVANT

• If RYBREVANT dosing on Day 1 of the cycle was delayed, but retreatment criteria for chemotherapy were met, dosing with chemotherapy was continued as planned and patients were evaluated weekly for retreatment.⁵
• If RYBREVANT was delayed for ≥6 weeks from the last dose, a discussion was held with the Medical Monitor prior to re-dosing.⁵
• All study treatments were interrupted during a grade ≥3 adverse event (exception: for hematologic toxicities, RYBREVANT was interrupted only if there was grade 4 toxicity lasting for >7 days and/or grade 4 thrombocytopenia associated with bleeding or hospitalization or grade 4 febrile neutropenia).⁵
• If all treatments were delayed, patients were re-evaluated weekly for retreatment. Redosing with RYBREVANT proceeded after retreatment criteria were met, whether on Day 8 or Day 15 of the cycle. Chemotherapy and RYBREVANT could be resumed in the subsequent cycle after retreatment criteria for pemetrexed with or without carboplatin were met, as described above.⁵
• If RYBREVANT treatment was delayed from C1D1 to Day 2 and from C1D2 to Day 3, appropriate premedications were administered before RYBREVANT infusion.⁵
• If RYBREVANT dosing was delayed on Cycle 1 Day 8 and/or Cycle 1 Day 15, it was not made up. If dosing was delayed in Cycle 2 or beyond, then the dates of the subsequent dosing were scheduled based on the timing of the previous dosing of RYBREVANT.⁵
• Discussion with the Medical Monitor occurred prior to restarting protocol treatment.⁵

MARIPOSA-2 Study

Study Design/Methods

• Phase 3, ongoing, randomized, open-label study designed to assess the efficacy and safety of RYBREVANT-LAZCLUZE-chemotherapy (n=263) and RYBREVANT-chemotherapy (n=131) vs chemotherapy alone (n=263) in 657 patients with EGFR-mutated locally advanced or metastatic NSCLC on or after osimertinib monotherapy (as the most recent line of therapy).^6,7
  • RYBREVANT 1400 mg IV (1750 mg IV for baseline body weight ≥80 kg) was administered every week for the first 4 weeks, with the initial dose as a split infusion on C1D1 and D2, followed by 1750 mg IV (2100 mg IV for baseline body weight ≥80 kg) every 3 weeks starting at week 7 (C3D1) until disease progression.
  • LAZCLUZE 240 mg was administered orally (PO) once daily.
  • Chemotherapy was administered every 3 weeks at the beginning of each cycle, with carboplatin at AUC 5 IV for the first 4 cycles, and pemetrexed at 500 mg/m² IV until disease progression.
• In the RYBREVANT-LAZCLUZE-chemotherapy arm, patients randomized before November 7, 2022 received LAZCLUZE on C1D1. Due to an increase in hematologic and gastrointestinal toxicities in the arm, the regimen was modified to start LAZCLUZE after carboplatin completion.⁷
  • An open-label, randomized, extension cohort will evaluate the efficacy and safety of the modified RYBREVANT-LAZCLUZE-chemotherapy regimen vs RYBREVANT-chemotherapy.

The information below summarizes interventions investigators in the MARIPOSA-2 study were instructed to perform to manage RYBREVANT and/or chemotherapy dose delays.

Dose Delay Guidance

• When treatment delay was indicated, the chemotherapy and/or RYBREVANT dose could be delayed until recovery of toxicity to a level allowing continuation of treatment. A patient for whom treatment was delayed was to be assessed at least weekly to ensure adequate supportive care was being administered and to assess for improvement of toxicity.⁸
• Prior to restarting treatment, patients must have met retreatment criteria for chemotherapy and/or RYBREVANT in accordance with the product labeling, study protocol, and local guidelines.⁸

All Arms

• Chemotherapy:
  • If retreatment criteria were not met for carboplatin and/or pemetrexed, then retreatment was delayed by 1 week at a time.⁸
  • If chemotherapy administration was delayed >42 days (±3 days) from the last treatment, chemotherapy was discontinued unless continued treatment was approved by the sponsor.⁸
  • Carboplatin administration could not exceed a total of 4 cycles.⁸
• RYBREVANT-LAZCLUZE-chemotherapy arm:
  • For venous thromboembolism (VTE) events associated with clinical instability (eg, respiratory failure or cardiac dysfunction) in patients receiving the combination of RYBREVANT and LAZCLUZE, study treatment was held until the patient recovered from the event. Thereafter, the treatment could be resumed at the discretion of the investigator.⁸

RYBREVANT-LAZCLUZE-Chemotherapy and RYBREVANT-Chemotherapy Arms

• Chemotherapy:
  • If chemotherapy could not be administered on the scheduled day, dosing with RYBREVANT was continued as planned, if RYBREVANT retreatment criteria were met.⁸
  • If chemotherapy was delayed by a week (eg, administered on Day 8 of the cycle) subsequent cycle dosing of RYBREVANT could be delayed by 1 week to align with the chemotherapy dosing schedule. Alternatively, if chemotherapy was delayed by 2 weeks (eg, administered on Day 15 of the cycle), then the subsequent cycle dosing of RYBREVANT could be accelerated by 1 week to align with chemotherapy.⁸
  • While some flexibility in the RYBREVANT dosing schedule was allowed as described above, combination chemotherapy had to be dosed at an interval of ≥21 days.⁸
• RYBREVANT:
  • If RYBREVANT dosing on Day 1 of the cycle was delayed, but retreatment criteria for chemotherapy were met, dosing with chemotherapy was continued as planned and patients were evaluated weekly for RYBREVANT retreatment.⁸
• RYBREVANT and chemotherapy:
  • If both chemotherapy and RYBREVANT had to be delayed, patients were re-evaluated weekly for retreatment. Dosing with RYBREVANT could proceed once retreatment criteria were met, whether on Day 8 or Day 15 of the cycle. The dosing of both chemotherapy and RYBREVANT could resume in the subsequent cycle once retreatment criteria for pemetrexed with or without carboplatin were met, as described above. The Medical Monitor was consulted if there were questions regarding restarting of protocol treatment after dose delays.⁸

Literature Search

A literature search of MEDLINE^®, Embase^®, BIOSIS Previews^®, and DerwentDrug File (and/or other resources, including internal/external databases) was conducted on 17 September 2026.

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. A randomized, open-label phase 3 study of combination amivantamab and carboplatin-pemetrexed therapy, compared with carboplatin-pemetrexed, in patients with EGFR exon 20ins mutated locally advanced or metastatic non-small cell lung cancer. In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000- [cited 2026 September 17]. Available from: https://clinicaltrials.gov/study/NCT04538664 NLM Identifier: NCT04538664.

4. Zhou C, Tang KJ, Cho BC, et al. Amivantamab plus chemotherapy in NSCLC with EGFR exon 20 insertions. N Engl J Med. 2023;389(22):2039-2051.

5. Zhou C, Tang KJ, Cho BC, Liu B. Clinical Protocol for: Amivantamab plus chemotherapy in NSCLC with EGFR exon 20 insertions. N Engl J Med. 2023;389:2039-2051.

6. Janssen Research & Development, LLC. A phase 3, open-label, randomized study of amivantamab and lazertinib in combination with platinum-based chemotherapy compared with platinum-based chemotherapy in patients with EGFR-mutated locally advanced or metastatic non-small cell lung cancer after osimertinib failure. In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000- [cited 2026 September 17]. Available from: https://clinicaltrials.gov/study/NCT04988295 NLM Identifier: NCT04988295.

7. Passaro A, Wang J, Wang Y, et al. Amivantamab plus chemotherapy with and without lazertinib in EGFR-mutant advanced NSCLC after disease progression on osimertinib: primary results from the phase III MARIPOSA-2 study. Ann Oncol. 2024;35(1):77-90.

8. Passaro A, Wang J, Wang Y, et al. Clinical Protocol for: Amivantamab plus chemotherapy with and without lazertinib in EGFR-mutant advanced NSCLC after disease progression on osimertinib: primary results from the phase III MARIPOSA-2 study. Ann Oncol. 2024;35(1):77-90.