Joshua M. Bauml, MD

Treating patients who are progressing on a first-line tyrosine kinase inhibitor [TKI] for 

-positive non–small cell lung cancer is very tricky. We have data on some second-line TKIs, most notably lorlatinib is approved in this space. The approval for lorlatinib officially depends upon which TKI was used in the first line. Functionally, I do not change what I use in the second line. If we look at mechanisms of resistance to first-line TKI, the most common 

-based mutation is G1202R; it is much more common with alectinib and brigatinib than it is with crizotinib. Lorlatinib is the only drug on the market that has substantial activity on G1202R in vitro. Though I will say that in vivo in humans it does seem like brigatinib has some efficacy. If I have a patient who’s on crizotinib, develops G1202R, I might be more likely to reach for brigatinib than I will to reach for lorlatinib based on the fact that brigatinib tends to be better tolerated, in my experience. Understanding this mutation is very important. If we look at the lorlatinib study, the response rate in the later lines of treatment after prior TKIs is double in a patient who has an 

-based resistance mutation to what it is in a patient who does not have an 

-based resistance mutation. Any time I have a patient who is on an ALK TKI or an EGFR TKI, I do a repeat molecular testing, often utilizing liquid biopsy. If the liquid biopsy is not illuminating, I will often reach for a tumor biopsy to better understand why a patient is progressing.

+ non–small cell lung cancer remains a major problem for our patients around the world. There have been so many advances in terms of ALK TKIs; however, to me the critical element that is still missing is the fact that we have these highly active drugs and yet resistance is inevitable. We must figure out a way to overcome and prevent that resistance so our patients can have prolonged disease responses and hopefully one day cures as well.

A 57-year-old man presented with fatigue, anorexia, and occasional rib pain

PE: mild right-sided chest tenderness on palpation 


Chest x-ray showed multiple right upper lobe masses

Chest/abdomen/pelvic CT scan confirmed 3 masses (largest 6.5 cm)

PET scan showed activity in the right upper lobe masses

MRI of the brain showed multiple scattered lesions, consistent with multifocal brain

Bronchoscopy with transbronchial biopsy of the right upper lobe mass confirmed lung adenocarcinoma, invasive mediastinal

ALK fusion+, EGFR-, ROS1-, BRAF-, KRAS-, NTRK-, MET-, RET

Patient was started on brigatinib 90 mg qDay for 7 days; well tolerated; dose was increased to 180 mg qDay

Videos

Managing patients with who progress on a TKI, the role of re-biopsy at progression of disease, and the future treatment landscape for ALK+ mNSCLC. 

Second-line and Beyond: Treatment of ALK+ mNSCLC

: The ALTA-1L trial compared brigatinib at the dosing of 90 mg for the first 7 days followed by a dose escalation to 180 mg daily, if they tolerate it, compared to crizotinib. We found in that study that there was a remarkable improvement in progression-free survival with brigatinib, and there was a particularly great improvement in the incidence of brain metastases as a result of use with brigatinib. That’s not surprising given the fact that brigatinib has excellent CNS [central nervous system] penetrance, while crizotinib is relatively poor at that.

One of the concerns people have with the use of brigatinib is a pulmonary event; sometimes people erroneously call this pneumonitis, however it’s really not pneumonitis. There’s been wonderful work done on this by [Ross] Camidge, [MD, PhD,] at the University of Colorado. He found, along with his colleagues, in a paper published in the 

was that this is a pulmonary event. The distinction here is that pneumonitis implies there’s inflammation, and it further implies that if you stop the drug, it will get better. It turns out that both of those features do not apply to these pulmonary events. Giving steroids has no impact on the incidence of these events, and the best way to manage it, provided the patient is stable, is to continue treating through it. Then the patient can overcome it and continue to receive brigatinib safely the vast majority of the time. There’s been some recent work that Dr Camidge has led that has found these sorts of pulmonary events may be more common than what we see clinically if you look at pulmonary function test changes. But they seem to be brief and are not limiting in terms of causing severe toxicity for the vast majority of patients. If you look at the quality of life in the ALTA-1L study, you can see that brigatinib was associated with a better quality of life than crizotinib. However, it’s difficult to separate that from the simple fact that patients were responding longer to the treatment, and that is always associated with an improved quality of life.

A review of the open-label, phase 3 ALTA-1L trial comparing the use of brigatinib to crizotinib in ALK+ metastatic non-small-cell lung cancer. 

ALTA-1L Trial in ALK+ mNSCLC 

: There are multiple tyrosine kinase inhibitors approved for first-line management of 

-positive non–small cell lung cancer. When I look at them, there are 2 classes; the older drugs, crizotinib and ceritinib, which don’t have a lot of CNS [central nervous system] penetration, and the newer drugs approved in the first line, notably alectinib and brigatinib. Alectinib and brigatinib are both highly CNS penetrant ALK inhibitors, which are highly effective in the treatment of 

+ non–small cell lung cancer. In the ALTA-1L study, brigatinib was found to be superior to crizotinib in terms of progression-free survival. In the ALEX study, the same finding was found for alectinib as compared to crizotinib.

How do I decide which one to use? Honestly, I think either are completely reasonable; it ends up being a bit of a coin flip in terms of which treatment we would use. The toxicity profile is a little different between these agents. Alectinib seems to have a higher rate of liver function test elevations, whereas brigatinib has a rare pulmonary event that happens usually early in the treatment. In terms of how we incorporate brain metastases into that treatment decision algorithm, both alectinib and brigatinib are highly CNS penetrant. If I have a patient who has brain metastases and if they’re asymptomatic and relatively small, I will often start with a tyrosine kinase inhibitor and follow closely with my colleagues in radiation oncology to ensure that the patient is having a nice response in the brain. I follow these patients very closely; I tend to see them in my medical oncology clinic about every 6 weeks, once with the nurse practitioner I work with, and then alternating with a scan and a visit with me. Then when we compare that to the radiation oncology follow-up for brain metastases, it’s dependent on how the brain metastases are working; I work closely with my colleagues in radiation oncology for that scheduling.

Approaching TKI (tyrosine kinase inhibitor)-based therapy for the first-line management of ALK+ mNSCLC. 

First-line Treatment Options for ALK+ mNSCLC 

: Today we’re going to talk about a case of a 57-year-old man who presented with fatigue, anorexia, and rib pain. His past medical history was unremarkable; he was a relatively healthy patient who had laboratory test results that were within normal limits. However, he did have some right-sided chest tenderness on palpation, and a chest x-ray revealed multiple right upper-lobe masses. A CT scan showed 3 masses, with the largest being 6.5 cm, and a PET [positron emission tomography] scan showed they were avid. An MRI of the brain showed multiple metastases. He had a bronchoscopy with endobronchial ultrasound, which showed adenocarcinoma involving mediastinal lymph nodes as well as the masses. He was staged as having stage IV non–small cell lung cancer. He had a good performance status: PS0. He also had a molecular testing profile, which revealed an 

 fusion, and the remainder biomarkers were negative; 

. And PD-L1 was also negative. This patient was started on brigatinib initially 90 mg daily for 7 days as per the label, and then was dose-escalated to 180 mg daily as per standard of care.

What other kind of test can we do? There are some single gene tests that are utilized, such as PCR [polymerase chain reaction] for mutations and FISH [fluorescence in situ hybridization] for translocations or fusions. My preference is to use next-generation sequencing, utilizing a DNA-based approach for mutations, and an RNA-based approach for translocations and fusions. We’ve found that by incorporating both tests, we are able to identify significantly more patients who have molecular driver alterations.

Joshua M. Bauml, MD, presents the case of a 57-year-old man with ALK fusion+ non-small-cell lung cancer (NSCLC) and discusses recommended molecular tests to identify patients with molecular driver alterations. 

Joshua M. Bauml, MD | Authors

Articles

Second-line and Beyond: Treatment of ALK+ mNSCLC

ALTA-1L Trial in ALK+ mNSCLC

First-line Treatment Options for ALK+ mNSCLC

Case Overview: 57-Year-Old Man With ALK+ NSCLC