New Agent Investigated for Patients With RET Fusions Given a Prior RET Inhibitor

Though selpercatinib (Retevmo) and pralsetinib (Gavreto) were developed and approved by the FDA to help treat patients with RET fusion-positive non-small cell lung cancer (NSCLC) medullary thyroid cancer (MTC) within the past few years, a need remains for the development of more RET inhibitors.

According to Nathan Pennell, MD, PhD, RET fusions occur in around 1-2% of lung adenocarcinomas and 10-20% of papillary thyroid carcinomas, and activating RET mutations are found in 50-60% of medullary thyroid cancers (MTC). While existing RET inhibitors can help patients with these mutations, resistance often occurs, including solvent front and gatekeeper mutations.

Because of this resistance, LOXO-260, a highly potent and selective inhibitor of RET, was developed to act against both solvent front and gatekeeper mutations, whether they are expressed alone or together. LOXO-260 maintains potency against RET fusions or mutations.

LOXO-260 is being evaluated in the global, open-label, first-in-human, phase 1 LOXO-NGR-21001 study (NCT05241834) in patients with locally advanced, unresectable and/or metastatic cancers including NSCLC and MTC with a RET fusion or activating RET mutation who have had previously received a selective RET inhibitor. The trial consists of 2 parts: the phase 1a dose escalation portion and the phase 1b dose expansion portion to evaluate LOXO-260 in a RET fusion-positive NSCLC, thyroid cancer, RET-mutant MTC.

The primary end point of the dose escalation portion of the trial is to establish a maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D), as well as to determine the safety of LOXO-260. Secondary end points consist of pharmacokinetics (PK) and preliminary antitumor activity of LOXO-260 per RECIST v1.1. For the dose expansion portion of the trial, the primary end point is to assess the antitumor activity of LOXO-260 based on investigator-assessed overall response rate, and secondary end points include characterizing the PK and antitumor activity of LOXO-260 based on progression-free survival (PFS), time to response, and duration of response (DOR).

In an interview with Targeted Oncology^TM, Pennell, a medical oncologist at the Cleveland Clinic, discussed the basis of the LOXO-NGR-21001 trial evaluating the safety, adverse events (AEs), and effectiveness of LOXO-260 in patients who have previously received a prior selective RET inhibitor.

Targeted Oncology^TM: What previous research have we seen in regard to RET gene fusions and mutations?

Pennell: We know that certain types of lung cancer—lung adenocarcinoma—are caused by fusion genes in the RET gene, as well as mutations in medullary thyroid carcinoma in the RET gene, and [these genes] can lead to cancers progressing. There has been an effort to develop inhibitors of the RET protein. A couple of years ago, the first selective RET inhibitor called selpercatinib was developed by Loxo Oncology. We participated in that trial and it became approved by the FDA for treatment of advanced NSCLC and MTC with either a RET mutation or RET fusion.

However, we now know that some [patients] develop resistance to selective RET inhibitors. There have been a couple of specific kinds of acquired resistance mutations, known as either solvent front mutations, or a second type of mutation called gatekeeper mutations which can develop in [patients] and cause resistance to drugs like selpercatinib. LOXO-260 is a newer drug that was developed specifically to be able to overcome those secondary mutations and for [patients] who develop resistance to the first-generation drugs.

We are participating in a first-in-human, phase 1, dose-escalation study in RET-positive NSCLC as well as other types of solid tumors. Once we reach a maximum tolerated dose, there will then be expansion cohorts, both in MTC with RET mutations and RET fusion-positive lung cancer to try to determine how effective it is in people who develop resistance to the previous RET inhibitors.

What was the basis of the trial?

Loxo [Oncology], the company that makes selpercatinib, has been very active in helping to develop drugs against resistant RET-mutant lung cancer and other tumors, and as science was coming out, showing the new mutations that cause resistance to the other drugs. They, and some other companies, have been developing new drugs specifically to try to overcome those mechanisms of resistance.

The basis of this trial is that there are people out there who need these options, and that this drug seems to be promising. Obviously, with a brand-new drug, you have to start with a phase 1 trial to make sure that it is safe and figure out what the appropriate dose is, but that is the rationale for the study.

What baseline characteristics were required for enrollment in this trial?

There are 2 parts of the trial, phase 1a and phase 1b. The initial phase 1a which is open now is for any cancer that has a RET mutation or a RET gene fusion. Most of those will end up being [patients with] lung cancer because that's the most common type of cancer with RET fusions, or MTC, or other types of thyroid cancer with rare mutations.

They have to have incurable stage IV disease and then they have to have progressed after prior treatment with a selective RET inhibitor like selpercatinib or pralsetinib. They have to have already received the most appropriate standard treatment, and then have moved on to needing another option.

What are the primary end points and the main goals of the study?

The main goal of the phase 1 study is to determine the MTD and to determine the RP2D. Secondary end points include what the response rate is in [patients who are resistant to prior therapy], [and] what the PFS, overall survival, DOR, and more [are]. [Also,] what are all the [AEs] of the drug since it's a brand-new drug? We don't yet know

How has the treatment landscape for this patient population changed over the past few years?

They have been recognized as a subtype of lung cancer for many years. However, the older drugs like the first-generation drugs, just did not work very well. They had a lot of toxicities and they weren't specific for RET. Specifically, they covered a lot of other types of tyrosine kinases in addition.

The approval of selpercatinib and pralsetinib have really revolutionized treatment of these patients. Now with very minimal AEs, one is able to get durable responses that can sometimes last years. I've seen patients’ lives transformed by being able to access these drugs. The downside, of course, is that it is still not a cure, and unfortunately, these patients go on to develop resistance at some point, so they definitely need more options.

What unmet needs still exist in this space?

The major unmet need is for another option when patients develop resistance to the initial drugs like selpercatinib and pralsetinib. Right now, if [patients] are treated with those drugs and then develop resistance, we are left with very old options like chemotherapy, which don't last very long. We are understanding more about how [patients] develop resistance and how tumors develop resistance to the first-generation drugs or the selective RET inhibitors, so we need to continue to find better options for those patients.

What do you most look forward to learning more about in this research? What excites you for the future of space?

The exciting thing about drugs like LOXO-260 are that these are drugs that basically come directly from information from people with cancer who develop resistance. So real people with advanced lung cancer who are benefiting from targeted treatments, but then whose cancer gets worse anyway, have biopsies done, learn what's changed, and then based on that, they have designed drugs to overcome those elements of resistance, the new mutations.

Being able to see that translational bench-to-bedside research is really exciting to be able to, within a few years of the first drugs being developed, develop the next generation of drugs. To be a part of that is really exciting, and hopefully it will help our patients. I think it's a very promising drug and we want to get the word out that it's available so that people out there who need that option can access it.

Reference:

Pennell NA, Wirth LJ, Gainor JF, et al. A first-in-human phase 1 study of the next-generation RET inhibitor, LOXO-260, in RET inhibitor refractory patients with RET-altered cancers (trial in progress). J Clin Oncol. 2022;40(suppl 16):abstr TPS8595. doi:10.1200/JCO.2022.40.16_suppl.TPS8595