Never smokers with advanced lung adenocarcinoma represent a growing population with genetic differences necessitating tailored therapeutic approaches. With the phase 2 HARMONIC trial (NCT05456256), investigators are hoping to build on early efficacy signals observed with the investigative agent LP-300 in combination with standard-of-care chemotherapy in a subgroup of never smokers.¹

“LP-300 was originally developed as a neuroprotective agent for chemotherapy,” Joshua Eric Reuss, MD, said. “It is a disodium salt that affects signaling pathways through modification of cysteine residues. In an original phase 3 trial [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.”

In an interview with OncLive, Reuss, a thoracic medical oncologist at MedStar Health, discussed the enrollment criteria for the HARMONIC trial, the demonstrated safety and efficacy of LP-300, and potential benefits of the agent for never smokers.^®

How does this agent work in combination with chemotherapies?

In the phase 2 HARMONIC study, [LP-300] is being investigated together with carboplatin and pemetrexed as this is the more common chemotherapy regimen we use in lung adenocarcinoma. Its mechanism of action andits ability to affect chemotherapy is multifold. 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.

Why may LP-300 have demonstrated efficacy with chemotherapy in the specific population of never smokers?

[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. 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.

Although this study did not have tissue to retrospectively [analyze] go back and look for these driver mutations, that is the area where there’s the most promise [as they] may indicate benefit. This compound has [also] been looked at preclinically. [For example,] there was a recent publication [that showed that in patients with] ALK-mutated NSCLC the LP-300 molecule helped to disrupt signaling pathways, which further reinforces the hypothesis that this molecule may be efficacious in patients with driver mutations.

What was the design of the HARMONIC study?

This is a randomized phase 2 clinical trial that is enrolling patients with lung adenocarcinoma who have driver mutations, are never smokers, and have progressed on prior targeted therapy. Patients are enrolled and randomly assigned 2:1 to the combination of carboplatin with pemetrexed and LP-300, or carboplatin [and] pemetrexed alone. [They will] receive 6 cycles of therapy with the option to then continue pemetrexed maintenance [and] coprimary end points are progression-free survival and overall survival.

Do you anticipate any barriers to enrollment for this specific study?

There are some positives and negatives to this trial. A pertinent positive is that [enrollment criteria] encompasses different driver mutation subsets…. If a site doesn’t have the ability to have a specific ALK-, MET-, RET,- or an EGFR-driven study, then this is potentially a good option.

However, that is also a limitation. A lot of trials are now focusing on next-generation targeted therapies to overcome specific mechanisms of resistance or to target specific pathways that appear to be upregulated or altered in the setting of therapy resistance. That is a potential negative of this study as once a patient has progressed on targeted therapy, whether the oncogenesis that drives cancer growth in that patient is still dependent on that signaling pathway depends on the mechanism of resistance.

With immunotherapy available for patients who progress on targeted agents, what is the incentive for patients to enroll in this study?

We know that a lot of mutational subgroups tend to be refractory to immunotherapy; that has been studied in the frontline setting and several tumor types as well as in the subsequent line setting. Outside of an appropriately designed immunotherapy clinical trial, we have little evidence to suggest that immunotherapy monotherapy is an appropriate treatment for patients with driver mutations.

There are data on combination VEGF blockade as well as the combination of immunotherapy with VEGF [inhibition] and chemotherapy, but the ability to receive immunotherapy by itself I don’t view as a particular impedance to this clinical trial. One thing that is worth noting, is that to participate in this trial one would have to stop the targeted therapy that they’re [receiving] and there can be a site-specific progression on targeted therapy. For example, if a patient has ongoing CNS [central nervous system] control from a targeted therapy that has strong CNS penetration but has progression [elsewhere] in the body, [once] they stop targeted therapy, a potential concern is that they might lose control of disease in the CNS. [That is one concern] for a trial of this design.

What are some of the early safety signals that have been seen and how safety is being analyzed in the study?

This is an agent that was designed to limit adverse effects, so the [toxicity] profile, at least from early studies, appears to be quite well tolerated. Mild IV [intravenous] site discomfort, thirst, and nausea were reported in early phase trials.

HARMONIC starts with a 6 patient safety lead in. 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.