FDA Backs Protocol Changes for LP-300 Trial in Non–Small Cell Lung Cancer

The FDA has raised no objections to major protocol modifications for the ongoing phase 2 HARMONIC trial (NCT05456256), which evaluates the investigational small molecule LP-300 (formerly known as biosustained disodium succinate) in never-smokers with advanced non–small cell lung cancer (NSCLC) adenocarcinoma. Lantern Pharma Inc, the sponsor, announced the feedback following a type C meeting request, providing a revised regulatory framework intended to target a molecularly defined patient subset. The trial will transition from a randomized design to a single-arm study exclusively enriching for patients harboring EGFR exon 21 L858R mutations who have experienced disease progression after tyrosine kinase inhibitor (TKI) therapy.¹

The protocol amendments alter both the patient population and the dosing schedule.Future enrollment will focus entirely on the EGFR exon 21 L858R mutation subset. This genomic variant represents roughly 40% of EGFR-mutant NSCLC globally and up to 50% in Asian populations, a cohort that historically exhibits lower TKI binding affinity and inferior clinical outcomes on standard therapies like osimertinib (Tagrisso) compared to those with exon 19 deletions. Additionally, the FDA raised no objections to extending the maximum duration of LP-300 administration from 6 to 8 cycles when given alongside a standard chemotherapy backbone of carboplatin and pemetrexed.

The shift to a single-arm, enriched design reflects the operational difficulties of maintaining a traditional randomized chemotherapy control arm in a heavily pretreated, niche patient population. Preliminary data from the trial prompted the strategic pivot. Multivariable Cox regression analyses adjusting for race, sex, and TP53 mutation status identified the L858R mutation as an independent predictor of progression-free survival (PFS) benefit. In early readouts, the EGFR exon 21 L858R cohort demonstrated a median PFS of 8.3 months when treated with the LP-300 triplet regimen.

A primary clinical objective of the amended trial layout is establishing a differentiated safety profile relative to current post-TKI standards of care. In the phase 3 MARIPOSA-2 trial (NCT04988295), the combination of amivantamab (Rybrevant) and chemotherapy—an FDA-approved regimen in the post-osimertinib setting—demonstrated significant toxicity, including a 23% rate of treatment-related serious adverse events (SAEs) and a 65% rate of adverse events leading to dose delays.² By comparison, preliminary safety data from 31 patients in the HARMONIC trial showed a 3% rate of treatment-related SAEs and a 19% rate of treatment-emergent AEs leading to dose delays. Infusion-related reactions and severe rash were reported at 7% in the LP-300 cohort, compared with 58% and 43% respectively in the historical amivantamab data.

The HARMONIC trial is actively enrolling patients across clinical sites in the United States and Taiwan, following the completion of targeted enrollment in Japan in July 2025. In early safety lead-in cohorts in the United States, the triplet regimen achieved an 86% clinical benefit rate and a 43% objective response rate among the first seven patients, including one durable complete response lasting over 2 years. Additional clinical data updates reflecting outcomes under the newly amended protocol are expected in the second half of 2026.

REFERENCES

1. Lantern Pharma Announces Successful Outcome of FDA Type C Meeting Request for HARMONIC™ Phase 2 Trial of LP-300 in Never-Smokers with NSCLC. News release. Lantern Pharma. May 19, 2026. Accessed May 22, 2026. https://tinyurl.com/dmbtndr4

2. Passaro A, Cho BC, Wang Y, et al. Amivantamab plus chemotherapy with or without lazertinib in EGFR-mutant advanced NSCLC after progression on osimertinib: primary results from the phase III MARIPOSA-2 study. Ann Oncol. 2024;35(1):77-90. doi:10.1016/j.annonc.2023.10.117