HARMONIC Evaluates Novel Combination in Growing Population of Never Smokers With Advanced Lung Cancer

Joshua Eric Reuss, MD

Never smokers represent a subgroup of patients with advanced lung cancer whose genetic makeup necessitates the need for targeted therapies and clinical trials aimed at improving outcomes. Compared with smokers, defined as those who smoke over 100 cigarettes in their life, never smokers have associated germline mutations for which targeted treatments may have demonstrative benefit.^1,2

The investigational agent LP-300, which was unable to statistically demonstrate activity as a treatment for the general population of patients with advanced non–small cell lung cancer (NSCLC), may hold some potential to address the unmet need in never smokers. In combination with standard-of-care carboplatin and pemetrexed, LP-300 will be evaluated in never smokers with NSCLC in the phase 2 HARMONIC study (NCT05456256).^2-4

“LP-300 was originally developed as a neuroprotective agent for chemotherapy,” Joshua Eric Reuss, MD, said in an interview with OncologyLive^®. “It is a disodium salt that affects signaling pathways through modification of cysteine residues. In an original phase 3 trial [DMS32212R; NCT00966914], [LP-300] was studied with cisplatin and paclitaxel or cisplatin and paclitaxel alone in advanced NSCLC [non–small cell lung cancer]. There was a promising signal of efficacy in patients who were never smokers, which prompted its subsequent development and investigation in patients with driver mutations.”

Finding a Role for LP-300

In the prior DMS32212R study, the 2-year survival rate for patients receiving cisplatin and paclitaxel was 30% with the addition of LP-300 compared with 25% for those who received chemotherapy alone among all treated patients (n = 288). In the subgroup of never smokers (n = 87), the 2-year survival rate was 63% for those receiving LP-300 with chemotherapy compared with 28% for those receiving chemotherapy alone (HR, 0.519; P = .0462). Among women treated in the study (n = 114), a 65% increase in 2-year survival was observed with the addition of LP-300, with rates of 51% compared with 31% for the combination and control arms, respectively (HR, 0.579; P = .0477). Finally, in a subgroup analysis of women who were never smokers (n = 66), the 2-year survival rates were 72% vs 32%, with the combination and chemotherapy alone, respectively (HR, 0.367; P = .0167).³

Reuss, who is a thoracic medical oncologist at MedStar Georgetown University Hospital and assistant professor in the Department of Medicine at Georgetown University Medical Center, in Washington, DC, noted that knowing this subgroup of patients have genetic markers, led investigators to hypothesize that the combination of LP-300 with chemotherapy would demonstrate clinical benefit. “[The efficacy was observed in a subgroup analysis, [and so] we must use some caution when looking at subgroup analyses from large trials retrospectively and trying to make inferences from that information,” he said. “However, knowing that there was a signal in never smokers, we do know that there is an enrichment of driver mutations in patients with NSCLC who are never smokers, including alterations in EGFR, ALK, ROS1, RET, to name a few.”

Reuss noted that the previous study did not have archival tissue samples for analysis.

LP-300 has a dual mechanism of action in addition to its ability to induce cysteine modifying activity on select protiens such as ALK and modulate protein function of EGFR, MET, and ROS1.³

“[The] mechanism of action [of LP-300] and its ability to affect chemotherapy is multifold,” Reuss said. “It helps to modulate oxidative stress, anti-angiogenesis, as well as reduced glutathione and thioredoxin–mediated tumor resistance to therapy. These are the mechanisms that are theorized to promote chemotherapy sensitivity and synergize with platinum-doublet chemotherapy.”

Additionally, the agent alleviates adverse effects (AEs) associated with chemotherapy. “This is an agent that was designed to limit AEs, so the [toxicity] profile, at least from early studies, appears to be quite well tolerated,” Reuss said. “Mild IV [intravenous] site discomfort, thirst, and nausea were reported in early-phase trials.”

HARMONIC Study Design

HARMONIC is a 2-arm, open label, randomized study that will evaluate 90 patients with NSCLC.^2,3 “HARMONIC starts with a 6-patient safety lead in,” Reuss explained. “The first 6 patients will be enrolled to evaluate safety and once the safety parameters are met, that’s when the subsequent randomization in the 2:1 fashion will happen.”

Approximately 60 patients will receive LP-300 plus standard-of-care pemetrexed and carboplatin and approximately 30 patients will receive standard of care alone.^2,3 The first patient is anticipated to be dosed by year end 2022 with enrollment lasting approximately 12 to 18 months.

Liquid biopsies will be taken at 4 points and data may be used to inform future trial designs.³

The trial is open to never smokers with lung adenocarcinoma who have disease progression on, unacceptable toxicities from, or are unable to tolerate treatment with tyrosine kinase inhibitors (TKIs). Their disease must be inoperable, stage III or IV, and they need to have an actionable genomic alteration such as MET exon14 skipping mutation, ALK, EGFR, NTRK, RET, or others.²

Additional criteria for enrollment include an ECOG performance status of 0 or 1, age of at least 18 years, and adequate bone marrow, hepatic, and baseline creatine levels. Patients who have documented stable central nervous system metastases are eligible for enrollment if they have no cognitive deficits, progressive sensory or motor deficits, or seizures in the 21 days prior to enrollment.²

In addition to the liquid biopsy, patients enrolling to HARMONIC must be willing to provide an archival tissue sample.

Patients randomly assigned to the LP-300 arm will receive 18.4 g/m² of LP-300 via IV over 30 minutes every 21 days for 6 cycles, in addition to pemetrexed and carboplatin. Following 6 cycles, patients will have the option to continue maintenance therapy with pemetrexed until disease progression, toxicity, or patient/physician discretion.

The primary end points are progression-free survival and overall survival. Secondary outcomes include objective response rate, duration of response, and clinical benefit rate.

The trial is open for enrollment.

References

1. Devarakonda S, Li Y, Rodrigues FM, et al. Genomic profiling of lung adenocarcinoma in never-smokers. J Clin Oncol. 2021;39(33):3747-3758. doi:10.1200/JCO.21.01691
2. A study of LP-300 with carboplatin and pemetrexed in never smokers with advanced lung adenocarcinoma (HARMONIC). ClinicalTrials.gov. Updated September 19, 2022. Accessed November 15, 2022. https://clinicaltrials.gov/ct2/show/NCT05456256
3. Lantern Pharma Inc corporate overview. Lantern Pharma. November 8, 2022. Accessed November 15, 2022. bit.ly/3g9rPHa
4. Lantern Pharma receives FDA authorization to initiate its phase 2 clinical trial, Harmonic, for LP-300 in never smokers with non-small cell lung cancer. News release. Lantern Pharma Inc. July 14, 2022. Accessed November 15, 2022. bit.ly/3AftTnO