Nathan A. Pennell, MD, PhD

Nathan Pennell, MD, PhD, vice chair of clinical research and director of lung cancer medical oncology at the Cleveland Clinic Taussig Cancer Center, discusses the importance of developing drugs based on resistance to previous treatments in patients with non–small cell lung cancer (NSCLC).

Pennell’s work on a phase 1 trial (NCT05241834) investigated LOXO-260, an agent designed based on drug resistance to the RET inhibitors selpercatinib (Retevmo) and pralsetinib (Gavreto) for patients with NSCLC and medullary thyroid cancer.

He says that this approach to drug development is based on studying real-world patients who initially respond but then progress on these agents due to resistance mutations. Doing biopsies on these patients for molecular profiling can show whether they have less expression of a gene or new mechanisms of resistance that are not present in untreated patients.

Pennell says that designing new drugs to fit unmet needs of first-generation targeted therapies is an exciting and important part of research, and having a new agent available for patients who relapse is a promising development.

 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.

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Nathan Pennell, MD, PhD, discusses the importance of developing drugs based on resistance to previous treatments in patients with non–small cell lung cancer. 

Lung Cancer Drugs in Development to Address Resistance Mutations

Nathan A. Pennell, MD, PhD, medical oncologist at the Taussig Cancer Center and professor of medicine at the Cleveland Clinic Lerner College of Medicine, discusses the importance of developing new RET inhibitors for patients with non–small cell lung cancer (NSCLC).

 alterations have been recognized as a biomarker in lung cancer, but older targeted therapies were less selective and had poor efficacy. The introduction of the selective RET inhibitors selpercatinib (Retevmo) and pralsetinib (Gavreto) made 

 a more significant biomarker in NSCLC, as well as in medullary thyroid cancer (MTC). While these therapies can sometimes offer years of clinical benefit, many patients develop resistance to RET inhibition.

Pennell says the major unmet need is a treatment option for patients who are resistant to selpercatinib and pralsetinib. There are no next-line options for these patients besides standard chemotherapy regimens for advanced NSCLC, which have limited efficacy in later lines of therapy.

 the novel RET inhibitor LOXO-260 in the ongoing phase 1 trial (NCT05241834) for patients with NSCLC and MTC.

 They have been recognized as a subtype of lung cancer and MTC for many years. However, the older drugs—the first-generation drugs—just did not work very well. They had a lot of toxicities, and they weren't specific for 

. Specifically, they covered a lot of other types of tyrosine kinases in addition.

In the last few years, with the approval of selpercatinib and pralsetinib, the other selective RET inhibitor—it’s really revolutionized treatment of these patients. Now, with very minimal adverse events, it 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.

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 really 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.

Nathan A. Pennell, MD, PhD, discusses the importance of developing new RET inhibitors for patients with non–small cell lung cancer.

Improving Outcomes for Patients With NSCLC and RET Alterations

Nathan A. Pennell, MD, PhD, co-director of the Cleveland Clinic Lung Cancer Program, vice chair of clinical research at the Taussig Cancer Center, and professor of medicine at the Cleveland Clinic Lerner College of Medicine, discusses the study design and goals of an ongoing phase 1 trial (NCT05241834) of a novel RET inhibitor for patients with non–small cell lung cancer (NSCLC) and medullary thyroid cancer (MTC).

The first-in-human phase 1 trial of the selective RET inhibitor LOXO-260 consists of phase 1a and phase 1b parts. In the phase 1a part, patients with any solid tumors with a 

 mutation were enrolled, the most common being NSCLC and MTC. Patients must have received a prior selective RET inhibitor such as selpercatinib (Retevmo) or pralsetinib (Gavreto) since LOXO-260 is intended to overcome resistance to prior RET inhibition.

The primary end point of the phase 1a study is to determine the maximum tolerated dose (MTD) and the recommended phase 2 dose (RP2D) within the first 28 days of treatment and secondary end points include pharmacokinetics and overall response rate (ORR). The phase 1b dose expansion part will evaluate efficacy end points including ORR, progression-free survival (PFS), overall survival (OS), and duration of response (DOR) as well as adverse events (AEs) related to treatment.

Pennell says that since this drug has never been tested clinically, its AE profile and efficacy are not yet known, and it is important to learn from the outcome of this trial.

There's 2 parts of the trial: phase 1a and phase 1b. The initial phase 1a, which is open now, is for essentially any cancer that has a 

 gene fusion. Most of those will end up being [patients with lung cancer] because that's the most common type of cancer with 

 fusions, or MTC or other types of thyroid cancer with 

 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. So they have to have already received the most appropriate standard treatment, and then have moved on to needing another option.

 The main goal of the phase 1 study is to determine the MTD and the RP2D. Secondary end points include: What is the response rate in resistant patients? What is the PFS, OS, DOR, etc? What are all the [AEs] of the drug since it's a brand-new drug and we don't yet know?

Nathan A. Pennell, MD, PhD, discusses the study design and goals of an ongoing phase 1 trial of a novel RET inhibitor for patients with non–small cell lung cancer and medullary thyroid cancer. 

Goals in the Phase 1 Study of a New RET Inhibitor for NSCLC and MTC

Nathan Pennell, MD, PhD, medical oncologist at the Taussig Cancer Center and professor of medicine at the Cleveland Clinic Lerner College of Medicine, discusses a first-in-human trial of a novel RET inhibitor for patients with non–small cell lung cancer (NSCLC) and medullary thyroid cancer (MTC).

The single-arm phase 1 trial (NCT05241834) of LOXO-260 enrolled patients with locally advanced, unresectable, or metastatic NSCLC, MTC, or other solid tumors with a documented 

 mutation who received a prior selective RET inhibitor.

According to Pennell, patients develop resistance to selective RET inhibitors such as selpercatinib (Retevmo) and pralsetinib (Gavreto) due to 2 types of resistance-linked mutations called solvent front mutations and gatekeeper mutations. The oral agent LOXO-260 was developed to overcome resistance to first-generation RET inhibitors with activity against both of these types of resistance mutations, whether they are present individually or together.

The dose escalation part of the trial is designed to determine the maximum tolerated dose and recommended phase 2 dose of LOXO-260 and monitor for safety and preliminary antitumor activity. The dose expansion part will measure the antitumor activity and pharmacokinetics of this agent based on progression-free survival, time to response, and duration of response.

 We now know that some people develop resistance to selective 

 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 people and cause resistance to drugs like selpercatinib and pralsetinib. And so LOXO-260 is a newer drug that was developed specifically to be able to overcome those secondary mutations in people who develop resistance to the first-generation drugs. We are participating in a first-in-human phase 1 dose-escalation study in 

-positive NSCLC as well as other types of solid tumors.

Nathan Pennell, MD, PhD, discusses a first-in-human trial of a novel RET inhibitor for patients with non–small cell lung cancer and medullary thyroid cancer. 

Trial of New RET Inhibitor Aims to Overcome Resistance in NSCLC and MTC

Nathan A. Pennell, MD, PhD, director, Lung Cancer Medical Oncology Program, Taussig Cancer Institute, Cleveland Clinic, discusses the role of molecular testing when treating and managing patients with

He shares his advice on what to do for patients who need therapy immediately, as well.

Molecular testing should be done upfront as quickly and efficiently as possible in all patients with nonsquamous non-small cell lung cancer. In the case that a physician is unable to get molecular testing done quickly and needs to initiate treatment early, Pennell recommends staying away from immunotherapy until the testing results are in.

There are 2 main consequences to not obtaining molecular testing results for patients with lung cancer, Pennell says. First, the patient may end up missing out on a very effective therapy based on their mutational status. Second, it is known that immunotherapy can cause significant toxicity in patients harboring an&nbsp;

mutation, which is why Pennell advises against using immunotherapy prior to receiving molecular testing results.

Nathan A. Pennell, MD, PhD, discusses the role of molecular testing when treating and managing patients with&nbsp;<a>lung cancer.</a>&nbsp;He shares his advice on what to do for patients who need therapy immediately, as well.

Nathan A. Pennell, MD, PhD | Authors

Articles

Lung Cancer Drugs in Development to Address Resistance Mutations

Improving Outcomes for Patients With NSCLC and RET Alterations

Goals in the Phase 1 Study of a New RET Inhibitor for NSCLC and MTC

Trial of New RET Inhibitor Aims to Overcome Resistance in NSCLC and MTC

Evaluating the Role of Molecular Testing in Lung Cancer