Elucidating Lorlatinib Benefit, ALK TKI Sequencing in ALK-Positive NSCLC

Jonathan W. Riess, MD, MS, director of Thoracic Oncology and associate professor of Medicine at UC Davis Comprehensive Cancer Center.

CancerNetwork® spoke with Riess, director of Thoracic Oncology and associate professor of Medicine at UC Davis Comprehensive Cancer Center, about the safety and efficacy of lorlatinib, a third-generation ALK tyrosine kinase inhibitor (TKI), based on results from the phase 3 CROWN trial. Furthermore, Riess discussed sequencing for ALKTKIs in later lines of therapy, other developments in the field for ALK-positive NSCLC, and strategies for mitigating adverse effects (AEs), particularly as they related to dose reduction.

Initially, Riess outlined the phase 3 CROWN trial, which compared lorlatinib and crizotinib (Xalkori) head-to-head, highlighting post hoc results presented at the 2024 ASCO Annual Meeting showing that the median progression-free survival (PFS) was not reached after 5 years with lorlatinib vs 9.1 months with crizotinib. He further expressed that lorlatinib may help address an unmet need for effective treatment in patients with ALK-positive lung cancers, which proportionally encompasses patients with minimal or no smoking history.

Furthermore, Riess compared the AE profile of lorlatinib with other first-line treatments for ALK-positive NSCLC, including alectinib (Alecensa), which Riess also considers using as a first-line treatment in this indication. He touched upon key takeaways from the CROWN trial, emphasizing that ALK mutations were not detected with circulating tumor DNA (ctDNA) testing, which he suggested has implications for sequencing subsequent lines of therapy.

He further explained that he primarily considers using lorlatinib for first-line treatment but may consider alectinib based on differences in AE profiles. Riess touched upon other developments in treating patients with ALK-positive NSCLC and concluded by highlighting sustained efficacy with lorlatinib when dose reductions for AE mitigation were employed.

CancerNetwork: Lorlatinib was assessed among patients with ALK-positive NSCLC in the phase 3 CROWN trial. Can you touch upon the significance of the results?

The CROWN trial was pivotal in the treatment of ALK-positive lung cancer. It was a randomized, global phase 3 study looking at patients with metastatic NSCLC whose tumors harbor an ALK rearrangement. It was first-line [treatment]. Patients with asymptomatic brain metastases, even if they were untreated, were allowed. Patients were randomly assigned 1:1 to receive lorlatinib or crizotinib, a first-generation ALK TKI. [The] primary endpoint was PFS.

[Investigators] presented this past year at [the 2024 ASCO Annual Meeting]. A post hoc analysis at 5 years showed an impressive PFS benefit [with lorlatinib]. Median PFS at 5 years was not reached, [and] 60% of patients had not progressed. [These were] unprecedented results in lung cancer; the hazard ratio was 0.19. Again, the median PFS was not reached with lorlatinib vs 9.1 months with crizotinib—a very significant study. A lot of what underlies the benefit is the activity of lorlatinib in the central nervous system, where ALK-positive lung cancer often spreads to the brain, as well as lorlatinib’s activity against ALK rearrangement and a number of ALK-resistance mutations to previous ALK TKIs.

What unmet need does this therapy help to reduce?

The unmet need is effective activity against this oncogene-driven subset of NSCLC. ALK-positive lung cancer is approximately 4% of NSCLC, [with] a higher proportion of patients who do not have a big smoking history or who have not smoked––it is one of those kinds of non–smoking-associated oncogene drivers. There has been a number of ALK inhibitors in development, first crizotinib then alectinib, and brigatinib [Alunbrig], and ensartinib [Ensacove], all of which have beaten crizotinib head-to-head.

[With] lorlatinib, even though all those next-generation ALK drugs were compared to crizotinib and not head-to-head against each other, the magnitude of benefit here for PFS [was] 60% at 5 years. Whereas, for example, alectinib, which is also commonly used [for] first-line treatment as another next-generation ALK TKI, has a median PFS on the order of approximately 3 years. Given the magnitude of that PFS benefit, [lorlatinib] is currently the main first-line ALK TKI that I use.

How did the AE profile of lorlatinib compare with that of other first-line treatments for ALK-positive NSCLC, and were there any unexpected toxicities?

There are some unique AEs [such as] elevated lipids and some neurologic AEs. You also need to monitor liver function. There could be some edema. Other ALK TKIs have had pretty good AE profiles. [With] alectinib, I have to monitor liver function tests [LFTs]. There could be some weight gain as well, but overall, [it is] generally well-tolerated.

Again, the 2 main ALK TKIs I currently look at from my patients in the first line are alectinib and lorlatinib. It is a shared decision-making [process] with our patients in terms of the pros and cons, the AE profile within the context of the patient, and the magnitude of the PFS benefit that has been noted in the studies, including the exceptional PFS in the [phase 3 CROWN] study with 5-year follow up.

What should your colleagues take away from the phase 3 CROWN trial results?

One is the magnitude of the PFS benefit. Two is the intracranial activity. Three is an appreciation for the unique AE profile and managing those toxicities. [Additionally], what I thought was interesting in terms of the translational component of the study is that emerging ALK mutations were not detected in the ctDNA at the end of lorlatinib treatment. If you look at resistance to the other approved ALK TKIs, ALK mutations can often occur and help mediate resistance to the ALK TKI. With lorlatinib, at least in the ctDNA, they did not see that. It was mainly bypass tracks and other mechanisms of resistance. That has implications on what comes next in terms of targeted therapies after lorlatinib.

How does lorlatinib fit into the current treatment landscape, given 3 preferred first-line options for this patient group?

All studies [evaluating next-generation ALKTKIs] were positive vs crizotinib. Alectinib, brigatinib, and lorlatinib all showed a significant and substantial PFS benefit over crizotinib. Then, you have the recent FDA approval [for ensartinib, which also showed a] significant, substantial PFS improvement over crizotinib.²

For me, it is the magnitude of the PFS benefit, the magnitude of the intracranial activity, and an appreciation for the potential AEs. That is where I discuss these options with my patients. I often consider lorlatinib. There are other patients where looking at alectinib or [another ALK TKI] based on the AE profile and so forth may also make sense as a choice. I discuss these regimens with my patients who have ALK-positive [disease] in terms of selecting the best ALKinhibitor for them.

What other developments in ALK-positive lung cancers have the potential to change clinical practice?

In terms of developments in ALK-positive lung cancer, there are other next generation ALK inhibitors [being developed]. One I would highlight would be NVL-655, an ALKTKI that shows promising clinical activity. Results [from the phase 1/2 ALKOVE-1 trial (NCT05384626)] presented at the 2024 European Society for Medical Oncology (ESMO) Congress showed some exceptional clinical activity in a heavily pretreated patient population.³ That is another ALK inhibitor that shows promise and is [being evaluated] in clinical trials.

The other thing we need to do to advance the field for ALK-positive lung cancer is that unlike more smoking-associated lung cancers, ALK-positive lung cancers do not benefit from immune checkpoint inhibitors. [Figuring out] how we can make immunotherapy work better in ALK-positive lung cancer is a huge unmet need. There have been some vaccine-based approaches that look promising. They are under clinical trials. There is an ALK peptide, a vaccine that has some data about restoring immunogenicity in ALK-rearranged lung cancer, and there are other immunotherapy approaches that we need to work on for [patients with] ALK-positive [NSCLC].

Is there anything else related to the phase 3 CROWN trial or lorlatinib treatment for ALK-positive lung cancers that you would like to highlight?

The takeaway message is it was an impressive PFS benefit. Again, 60% [of patients being] progression-free at 5 years for metastatic lung cancer is phenomenal. [One has] to appreciate the potential AEs, some of the unique AEs, and manage and potentially adjust the medication accordingly.

One thing I did not mention [regarding] the AEs is that the FDA-approved dose is 100 mg daily. But [data] showed that early dose reduction to 75 mg did not appear to affect efficacy. That is one thing I would emphasize, especially given the neurologic AEs. I tend to start at the FDA-approved dose but de-escalate dosing quickly. There are some data for AEs; trial data provide some evidence to support that you are still maintaining good efficacy despite the dose reduction.

References

1. Solomon BJ, Liu G, Felip E, et al. Lorlatinib versus crizotinib in patients with advanced ALK-Positive non–small cell lung cancer: 5-year outcomes from the phase III CROWN study. J Clin Oncol. 2024; 42(29):3400-3409. doi:10.1200/JCO.24.00581
2. FDA approves ensartinib for ALK-positive locally advanced or metastatic non-small cell lung cancer. News release. FDA. December 18, 2024. Accessed April 8, 2025. https://tinyurl.com/yy8e6bd6
3. Drilon AE, Lin JJ, Johnson ML, et al. Phase I/II ALKOVE-1 study of NVL-655 in ALK-positive (ALK+) solid tumours. Presented at: 2024 ESMO Congress; September 13-17, 2024; Barcelona, Spain. Abstract 1253O.