Understanding the ALTA-1L Trial
Lyudmila Bazhenova, MD: Despite the fact that our ALK tyrosine kinase inhibitors [TKIs] are very effective, resistance eventually develops. As you can see from the alectinib trial, the median progression-free survival is 34 months. Based on the brigatinib trial, the median progression-free survival is about 29 months. Eventually, the patient will develop resistance.
The medication that we have and that has looked at extensively for use after failure from prior second-generation tyrosine kinase inhibitors is lorlatinib. Lorlatinib has shown a response rate of approximately 30% in patients who failed second-generation tyrosine kinase inhibitors.
The role of the biopsy is controversial at this point. In my practice, I do a post-progression biopsy for a couple of reasons. No. 1, small cell transformation has been described as a mechanism of resistance for ALK patients, and treatment for small cell transformation will be different. You would want to use chemotherapy rather than an ALK TKI as monotherapy. The second possibility is you can find a bypass pathway. Patients have been described to develop other molecular alterations as mechanisms of resistance, and you can consider targeting those. There’s also acquired on-target or ALK domain mutations that predict sensitivity to tyrosine kinase inhibitors.
In May 2020, the FDA approved brigatinib for patients with ALK-positive non–small cell lung cancer. This was based on the ALTA-1L trial. ALTA-1L took patients who were ALK TKI-naїve and randomized them to brigatinib versus crizotinib. Enrollment on that trial was based on local testing. Prior chemotherapy treatment was allowed, and 27% of the patients in that trial had received prior chemotherapy. The primary end point was blinded independent review committee progression-free survival.
The study showed that brigatinib is better than crizotinib in regard to progression-free survival. For example, the independent committee review of progression-free survival was 24 months with brigatinib versus 11 months with crizotinib. And the investigator-determined progression-free survival was 29 months with brigatinib versus 9.2 months with crizotinib.
Brigatinib was superior to crizotinib in patients with or without CNS [central nervous system] metastases. For example, the median progression-free survival for those patients was 24 months in the brigatinib arm and 5.6 and 13 months in the crizotinib arms—5.6 months was for the patients who had brain metastases, and 13 months was for patients without. Brigatinib was effective for patients with brain metastases, showing a confirmed intracranial response of 78% in the brigatinib arm versus a 29% response in the crizotinib arm.
In the ALTA-1L trial, brigatinib showed an overall response rate of 74%, versus 62% with crizotinib. Responses were durable, as expected with ALK tyrosine kinase inhibitors. Duration of response was not reached with brigatinib. It was about 13.8 months with crizotinib. Responses were also durable in CNS. Intracranial progression-free survival was 24 months in the brigatinib arm and about 5.6 months in the crizotinib arm.
The ALTA-1L trial safety outcomes were consistent with prior experience with brigatinib. The drug’s adverse effects are common to those of other ALK tyrosine kinase inhibitors. The most common adverse effect of brigatinib was diarrhea, at about 49%. The majority of those symptoms were early in grade, with only 1% of diarrhea reported as grade 3 and above. Increased blood CPK [creatinine phosphokinase] was also noticed in the brigatinib arm—at about 39%—and some of the cases were grade 3. Other notable adverse effects of brigatinib are nausea and some elevated transaminitis.
If one compares brigatinib versus crizotinib, you can see that excess toxicity with brigatinib was dominated mostly by amylase elevations, lipase elevations, and increases in CPK. It is important to note that amylase and lipase elevations with brigatinib are generally not associated with clinical symptoms of pancreatitis. In the crizotinib arm, excess toxicity was dominated by GI [gastrointestinal] symptoms; transaminitis; swelling, or edema; and visual effects.
In the brigatinib arm, dose reductions happened in about 30% of patients. A majority of those dose reductions were due to increased CPK. Some of them were due to increased lipase and increased amylase. The rest of the dose reductions were due to hypertension, rash, and pneumonitis.
Transcript edited for clarity.
Case: A 58-Year-Old Woman With ALK+ NSCLC
Initial presentation
- A 58-year-old woman presented with cough, fatigue and anorexia
- PMH: unremarkable
- PE: unremarkable
Clinical Workup
- Labs: WNL
- Imaging:
- Chest x-ray showed multiple left upper lobe mass and mediastinal lymphadenopathy
- Chest/abdomen/pelvic CT scan confirmed left upper lobe mass measuring 6.2 cm
- PET scan showed PET positivity in bilateral LUL mass and mediastinal LN
- MRI of the brain showed widespread scattered small lesions; consistent with multifocal brain metastases
- Bronchoscopy with transbronchial biopsy of the left upper lobe confirmed lung adenocarcinoma
- Molecular testing: ALK fusion+, EGFR-, ROS1-, BRAF-, KRAS-, NTRK-, MET-, RET-
- Staging: IVA adenocarcinoma; ECOG PS 1
Treatment
- Patient was started on brigatinib 90 mg qDay for 7 days; well tolerated; dose was increased to 180 mg qDay
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