Background
Collection of early-phase trials of novel agents for EGFR-mutant NSCLC after progression on osimertinib.
Patritumab deruxtecan (HER3-DXd): phase 1; N=57; prior EGFR TKI + chemo; HER3 antibody-drug conjugate (topoisomerase I payload).
Amivantamab + lazertinib (CHRYSALIS-2): single-arm; N=116 after osimertinib + platinum chemo, and a second cohort progressing on osimertinib without chemo. Amivantamab = EGFR-MET bispecific IgG1; lazertinib = 3rd-gen EGFR-TKI.
Telisotuzumab vedotin + osimertinib: phase 1/1b cohort E; N=25 c-Met-overexpressing EGFR+ NSCLC progressing on osimertinib. Teliso-V = anti–c-Met ADC (MMAE payload).
Patritumab deruxtecan (HER3-DXd): phase 1; N=57; prior EGFR TKI + chemo; HER3 antibody-drug conjugate (topoisomerase I payload).
Amivantamab + lazertinib (CHRYSALIS-2): single-arm; N=116 after osimertinib + platinum chemo, and a second cohort progressing on osimertinib without chemo. Amivantamab = EGFR-MET bispecific IgG1; lazertinib = 3rd-gen EGFR-TKI.
Telisotuzumab vedotin + osimertinib: phase 1/1b cohort E; N=25 c-Met-overexpressing EGFR+ NSCLC progressing on osimertinib. Teliso-V = anti–c-Met ADC (MMAE payload).
Interventions and follow up
HER3-DXd: 5.6 mg/kg IV q3w; mFollow up 10.2mo
Amivantamab + lazertinib: amivantamab 1050 mg IV (1400 mg if ≥80 kg) + lazertinib 240 mg PO daily; mFollow up 10.4mo (post-chemo cohort), 8.2mo (no-chemo cohort)
Teliso-V + osimertinib: teliso-V 1.9 mg/kg IV q2w + osimertinib 80 mg PO daily
Amivantamab + lazertinib: amivantamab 1050 mg IV (1400 mg if ≥80 kg) + lazertinib 240 mg PO daily; mFollow up 10.4mo (post-chemo cohort), 8.2mo (no-chemo cohort)
Teliso-V + osimertinib: teliso-V 1.9 mg/kg IV q2w + osimertinib 80 mg PO daily
Results
HER3-DXd ORR: 39% (26–52.4); responses regardless of resistance mechanism
HER3-DXd mDOR: 7.0mo (3.1–NE)
HER3-DXd mPFS: 8.2mo (4.4–8.3)
Amivantamab monotherapy (CHRYSALIS, Haura 2019): PR 28%, ORR 33%, mDOR 9.6mo
Ami + laz after osi alone (CHRYSALIS-2, Bauml 2021) ORR: 36%; mDOR 9.6mo; mPFS 4.6mo
Ami + laz by resistance: MET 75%, EGFR 27%, EGFR/MET-independent 0%, unknown 50%
Ami + laz after osi + chemo (CHRYSALIS-2, Chu 2022) ORR: 58%
Teliso-V + osi total ORR: 58%; c-Met 56% (high 50%, intermediate 63%); L858R 56%; Del19 67%
HER3-DXd mDOR: 7.0mo (3.1–NE)
HER3-DXd mPFS: 8.2mo (4.4–8.3)
Amivantamab monotherapy (CHRYSALIS, Haura 2019): PR 28%, ORR 33%, mDOR 9.6mo
Ami + laz after osi alone (CHRYSALIS-2, Bauml 2021) ORR: 36%; mDOR 9.6mo; mPFS 4.6mo
Ami + laz by resistance: MET 75%, EGFR 27%, EGFR/MET-independent 0%, unknown 50%
Ami + laz after osi + chemo (CHRYSALIS-2, Chu 2022) ORR: 58%
Teliso-V + osi total ORR: 58%; c-Met 56% (high 50%, intermediate 63%); L858R 56%; Del19 67%
Adverse events
HER3-DXd: Grade ≥3 AEs 34% (8% treatment-related); dyspnea 6%, pneumonia 3%.
Amivantamab + lazertinib: infusion reactions 65%, paronychia 49%, rash 41%.
Teliso-V + osimertinib: neuropathy 36%, nausea 20%, edema 20%.
Amivantamab + lazertinib: infusion reactions 65%, paronychia 49%, rash 41%.
Teliso-V + osimertinib: neuropathy 36%, nausea 20%, edema 20%.
Conclusions
Multiple novel agents (HER3-DXd, amivantamab + lazertinib, teliso-V + osimertinib) show activity after osimertinib failure, with responses partly tracking resistance mechanism. Phase 3 confirmation (e.g. MARIPOSA) was pursued.
Key Limitations
Early-phase, single-arm, small N; no randomized comparator; heterogeneous resistance mechanisms; cross-trial comparison not valid; immature survival data.
Clinical Context
Post-osimertinib resistance is a major unmet need. MARIPOSA-2 (amivantamab + chemo) gained FDA approval after osimertinib; HER3-DXd advanced to phase 3 HERTHENA-Lung01/02. ESMO endorses platinum-doublet chemo as standard after TKI failure, with novel ADCs and bispecifics emerging.