Treating ALK+ mNSCLC With ALK Inhibitors

Stephen Liu, MD: For the initial treatment of metastatic ALK-positive non–small cell lung cancer, we have several approved targeted agents, all better than chemotherapy. First came crizotinib, but over the past few years we have added ceritinib, alectinib, and most recently, brigatinib. Although all 4 are approved agents, alectinib and brigatinib are really the preferred choices in the first-line setting because of tolerability and CNS [central nervous system] penetration.

Brigatinib was initially approved in the salvage setting, just as ceritinib and alectinib were. It is notable that the progression-free survival with second-line brigatinib in the ALTA trial was 16.7 months. This is significantly longer than what has been seen with other TKIs [tyrosine kinase inhibitors] given in a similar setting.

Brigatinib was approved as first-line therapy on May 22, 2020, based on the phase 3 ALTA-1L trial. This was a large trial of 275 patients with treatment-naїve ALK-positive non–small cell lung cancer randomized to brigatinib or crizotinib. In this study, brigatinib was clearly the superior choice, with a much better progression-free survival. The hazard ratio was 0.49, and the response rate was quite high—at 79%. Therefore, brigatinib was clearly superior over crizotinib and is a first-line choice with excellent penetration within the brain. In fact, patients with brain metastases had particular benefit with the use of brigatinib.

Brigatinib is a selective ALK inhibitor. It is designed in a rational manner, where it retains activity in the setting of many solvent-front mutations that led to its high activity in the salvage setting and will hopefully lead to prolonged benefit in the frontline setting by preventing the development of resistance.

Brigatinib is administered orally as 1 pill daily. It is initially given as 90 mg per day for 1 week, followed by 180 mg daily provided there are no issues with tolerance.

When we think of choosing tyrosine kinase inhibitors for ALK-positive non–small cell lung cancer, the efficacy on brain metastases and duration of intracranial response is of critical importance. Brain metastases can be devastating events, and unfortunately this can be a very unforgiving site of relapse. It is critical that the choice of agents reflects activity within the brain. Using a CNS penetrant kinase inhibitor offers a clear advantage, not just for progression-free survival and overall survival but for quality of life as well. Efficacy on the brain must be considered in our choice of therapy.

Common toxicities of brigatinib largely include laboratory elevations. While we do see elevations in CPK [creatinine phosphokinase], lipase, and amylase, those have very little clinical consequence. In fact, off study, I don’t routinely check those. These are largely paper toxicities noted on the trial because they were sought. However, in someone without symptoms, they are really of unclear significance to me. Elevations in amylase and lipase in the absence of pancreatitis or symptoms of pancreatitis really have very little impact within my clinical practice. An elevation in CPK is not as concerning as someone with symptomatic cramps or myalgias. My monitoring is largely based on liver enzymes and symptoms.

Brigatinib does have a unique pulmonary toxicity. This is not really a pneumonitis. Rather, it is shortness of breath and oxygenation. By starting at 90 mg for 1 week before escalating to 180 mg, the incidence is quite low. And so it is typically our pattern to start with 90 mg daily. At 1 week, we check in with patients. Provided there are no concerning symptoms, we escalate to 180 mg. I’ve personally not seen any toxicity problems by using this approach.

Personally, my experience with brigatinib has been very favorable. I’ve used both brigatinib and alectinib in the frontline setting as my preferred agents. Both have very good CNS penetration and are well tolerated. One advantage of using brigatinib in the frontline setting is that it is 1 pill per day. Alectinib is another approved and very active agent. However, at full dose, it is 4 pills twice daily, which is quite a high pill burden. For a younger, active population, it can be very easy to forget doses. One pill a day does offer some advantages. When we think of how brigatinib performs in this space, it really fits the paradigm for precision oncology. Most patients respond very quickly and very well. Responses are deep and durable, and we have excellent CNS penetration. In addition, toxicity is very low, which means adherence is very high.

The pharmacokinetic data performed with brigatinib shows no relationship between exposure and certain lab abnormalities and no impact between exposure and time to dose reduction. If dose modifications are required for toxicity, I still feel very comfortable in terms of efficacy. In my opinion, adherence is often a surrogate for toxicity and tolerability. But adherence is also informed by convenience of dosing, and that is a clear advantage with brigatinib.

Transcript edited for clarity.

Case: A 57-Year-Old Man with ALK+ NSCLC

Initial Presentation

• A 57-year-old man presented with fatigue, anorexia and occasional rib pain
• PMH: unremarkable
• PE: mild right-sided chest tenderness on palpation
  
  

Clinical Workup

• Labs: WNL
• Imaging:
  • Chest x-ray showed 3 right upper lobe masses
  • Chest/abdomen/pelvic CT scan confirmed 3 masses (largest 7.3 cm)
  • PET scan showed activity in the right upper lobe masses
  • MRI of the brain showed widespread scatter small lesions; consistent with brain metastases
• Bronchoscopy with transbronchial biopsy of the right upper lobe confirmed lung adenocarcinoma
• Molecular testing: EML4-ALK fusion+, EGFR-, ROS1-, BRAF-, KRAS-, NTRK-, MET-, RET-, PD-L1 100%
• Staging: IVA adenocarcinoma; ECOG PS 0

Treatment

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