Ensartinib Looks to Find a Place in ALK+ NSCLC Paradigm Alongside Approved TKIs

As ensartinib (Ensacove) has recently joined the non–small cell lung cancer (NSCLC) paradigm where several ALK tyrosine kinase inhibitors (TKIs) are holding similar indications and have also bested the previous standard of care (SOC) crizotinib (Xalkori), physician experience with currently approved drugs will be crucial, according to Alberto Chiappori, MD.1,2

Version 3 of the 2025 NCCN Clinical Practice Guidelines in Oncology for NSCLC include ensartinib,1 which was FDA-approved in December of 2024,2 as a preferred category 1 first-line therapy option for patients with ALK-positive disease. The agent takes a place alongside alectinib (Alecensa), brigatinib (Alunbrig), and lorlatinib (Lorbrena), which have the same recommendations.1

“When you decide to choose 1 drug or another, the safety profile of the agent is what you will [use] as a major consideration [as] there are not data to prove that 1 is precisely superior to the other in [terms of] effectiveness,” Chiappori said in an interview with OncLive®.

Safety data showed that the most common adverse effects (AEs) observed with ensartinib in the phase 3 eXALT3 trial (NCT02767804), which supported the agent’s FDA approval, were rash (any-grade, 66.0%; grade 3 or 4, 12.0%), musculoskeletal pain (36.0%; 1.4%, respectively), cough (31.0%; 0.7%), constipation (31.0%; 0.0%), and pruritus (30.0%; 2.1%).3

“For example, [regarding the approved ALK TKIs], brigatinib has the toxicity of some respiratory dysfunction or shortness of breath,” Chiappori added. “Lorlatinib can elevate cholesterol [levels] and sometimes can cause some central nervous system [CNS] cognitive difficulties [that are] not necessarily permanent. We know that crizotinib had visual dysfunction. [With ensartinib], the main AE was skin rash, which other drugs have too, but each one has a differentiating AE. I’m not sure that any those [drugs have] AEs that you would say, ‘I would never use this drug in this patient because this is an absolute contraindication.’ I am personally not aware of any situation where you would say this is an absolute contraindication for this drug or these drugs.”

Furthermore, efficacy findings from eXALT3 showed that patients who received the agent (n = 143) achieved a median progression-free survival (PFS) of 25.8 months (95% CI, 21.8-not estimable [NE]) vs 12.7 months (95% CI, 9.2-16.6) with crizotinib (n = 147; HR, 0.56; 95% CI, 0.40-0.79; P = .0007).3 Additionally, the median overall response rates (ORRs) were 74% (95% CI, 66%-81%) vs 67% (95% CI, 58%-74%), respectively, with median durations of response of NE (95% CI, 22.0-NE) compared with 27.3 months (95% CI, 12.9-NE). The CNS ORRs were 59% (95% CI, 33%-82%) in the ensartinib arm (n = 17) vs 21% (95% CI, 7%-42%) in the crizotinib arm (n = 24).

In the interview, Chiappori detailed how to select between ensartinib and additional ALK TKIs that are approved in the NSCLC space, as well as important considerations to note with ensartinib’s FDA approval. Chiappori is a senior member of Oncology and Medicine for the Thoracic Oncology Program at the H. Lee Moffitt Cancer Center and Research Institute in Tampa, Florida.

OncLive: What is the significance of this FDA approval?

Chiappori: It emphasizes the importance of precision medicine. If you identify a target, and target [it] with an active agent, then the results are going to be positive. That’s the direction where oncology is going and should be going, not just in lung cancer or adenocarcinoma of the lung, but in every type of solid or [hematologic] malignancy. As to what it means in the context of what [agents] we already have available, what the difference [is will be determined with] time to some degree. Because these [FDA-approved] drugs are so effective, patients are doing very well. Twenty or 30 years ago, when I was a fellow, in 1 year or 2 years we knew if 1 treatment was better than the other because the benchmark was 1-year survival. [Now] we have drugs that allow patients to live 5 years. How can we tell [if] one is different or better than the other unless we wait at least 3 or 4 years?

People may [also] say, ‘why is it necessary to have 3 or 4 different drugs [approved] for the same indication?’ That’s certainly beyond just a simple medical question. [Ensartinib] is 1 more drug available for this group of patients and simplistically speaking, the more choices we have, the better off we all are.

How do you decide between agents as there are a plethora of options available for this indication?

That’s the question that everybody will ask. That answer is stratified into 2 levels. The highest, most important level is scientific evidence and based on the scientific evidence that exists right now, there has not been a direct comparison between any of these different agents. Claiming that 1 agent is superior to another would scientifically be a mistake. Nobody is going to compare these agents head-to-head. [Therefore], the scientific level is a level that we’re never going to have. We cannot claim that one [drug] is better than the other. What do we do then? We go to the second level.

The second level is a bit biased in the sense that it has to do with the opinion and experience of the treating physician. It may have a little to do with cost of the medicine, which usually, at least for a practice like mine which is a cancer center where I don’t have any private relation, is not something that [physicians are] involved with. It has to do with toxicities, comorbidities of the patient, [and] accessibility of the drug—nowadays, companies have patient programs that allow them to [get] the drug at lower prices, more accessible prices, or reduced doses.

At the end, the decision comes down to that. Probably the most important [considerations] at the medical level would be the doctor’s experience. Ensartinib was approved [in recent months and] we’ve had other drugs available [which have been] approved for years and have been using them for years. Will a doctor who has been using a drug for 5 years or more change to a different one that is newer where he/she cannot completely and scientifically assume that 1 is superior to the other?

Which patients were enrolled in eXALT3 and what was the trial seeking to assess?

The design of this trial resembled the design of the trials of previous drugs that had already obtained approval. Lorlatinib, alectinib, and brigatinib were all approved based on a design where the investigational agent was compared against crizotinib. Crizotinib was the first ALK TKI that was developed, and it was the SOC for a long time, until all these preceding phase 3 trials were completed and showed that the other drugs deserved to be included and became the standard.

One of the criticisms [for eXALT3 that] was elevated was why was it that they were comparing their drug against crizotinib [when] there were other drugs available that were already presumed to be superior or proven to be superior? I believe the strategy was to be consistent with what the precedent had been; all the previous [drugs] that had been approved, in the indication and the structure [of their studies], had used to crizotinib as the [comparator arm], and [the ensartinib study] did that [too]. That’s probably what the FDA was requiring, and that’s why the design of the study was like that. The design was consistent with what the precedent of prior similar indications [for similar] types of drugs had done before.

In regard [to patient characteristics], that was also very similar. Patients [had] advanced NSCLC, mostly stage IV [disease and] adenocarcinomas, [with] tumors that carry the ALK translocation. They allowed patients with brain metastases. Patients with ALK-translocated tumors have a propensity, maybe more so than a patient with general lung cancer, to develop brain metastases. All of these agents, somewhat less crizotinib than the newer generations, are drugs that have good CNS penetration [and] activity in the CNS. That is, to some degree, an important potentially differentiating factor of all these drugs. Therefore, it was important for the trial design to include those patients to have a sense of what the CNS activity of this agent is because that is a primary characteristic of the cancer, and it’s a primary characteristic in the efficacy of the alternative existing drugs.

What were key efficacy and safety data that led to the approval?

The primary end point of the trial was PFS, and a secondary end point was overall survival [OS]. I believe that the gold standard of an end point for any trial in general, particularly in stage IV lung cancer, should be OS. However, I recognize that if there is any exception to that, it is exactly this situation [for] patients who have a particularly identifiable predictive biomarker where many alternative treatment options exist; we have seen prior situations [where] patients in the control arm responded well initially to the drug, but [experienced disease progression] early, whereas those patients in the TKI [arm] took a much longer [time] to [relapse]. When you crossover treatment of the patients in the control arm to start receiving the effective ALK TKI, the survival of those patients is rescued. If you use OS as an end point, at the end [of the trial] the end point is likely to be similar because both groups of patients ended up taking the TKI and benefited from the efficacy of the TKI.

Recognizing the principle that the gold standard end point is OS, in this particular case, PFS is the appropriate end point, and was also the end point used in all the preceding studies. The precedent also had a major impact on this study’s [end points].

What advice would you give to colleagues about integrating ensartinib into their clinical treatment armamentarium?

The first step is that you have to be familiar with what [agents] you have had [available] until recently. I am familiar with how to use alectinib, brigatinib, and lorlatinib, and familiar with the outcomes that those drugs provide to patients and aware of the toxicity profiles. Then [you must] become familiar with ensartinib. That’s the first step, becoming familiar with all of those drugs. The second step would be to remember that we cannot scientifically claim that any of these drugs are superior to the other. Whether you choose 1 or the other will depend on your experience and knowledge of the data corresponding to each of those drugs.

The final thing that I would plan to do is use the [new] drug, [perhaps] in the next 1 or 2 patients, so that you can acquire some experience, familiarize yourself with the drug, and try to contrast it with the experience that you have from using the previous ones. That is not exactly what I would call a randomized phase 3 trial, which would be ideal to have, but I don’t believe we will ever have [1]. However, at least we’ll [have an] individualized experience creating a process where you can at the end, decide ‘yes, it is worth it for me to switch my practice’, or ‘no, it is not worth it for me to switch my practice.’ Or if you want, perhaps you could switch your practice in a particular circumstance.

References

1. NCCN. Clinical Practice Guidelines in Oncology. Non-small cell lung cancer, version 3.2025. Accessed March 3, 2025. https://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf
2. FDA approves ensartinib for ALK-positive locally advanced or metastatic non-small cell lung cancer. FDA. December 18, 2024. Accessed March 3, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-ensartinib-alk-positive-locally-advanced-or-metastatic-non-small-cell-lung-cancer
3. Ensacove. Prescribing information. Xcovery Holdings, Inc; 2024. Accessed March 3, 2025. https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/218171s000lbl.pdf