ALTA Trial for Relapsed/Refractory ALK+ NSCLC

Lyudmila A. Bazhenova, MD:My personal preference is brigatinib because it has the longest reported PFS [progression-free survival], currently stated at 15.6 months post crizotinib. Brigatinib covers the majority of the resistance mutations, so you don’t have to biopsy the patient. Although other options could be appropriate, such as alectinib and ceritinib.

The trial that led to brigatinib’s approval is called the ALTA trial. The ALTA trial took patients who had failed crizotinib and randomly assigned those patients to 2 arms. Arm A received brigatinib at 90 mg; arm B received brigatinib at 90 mg for 7 days, followed by dose escalation to 180 mg. The trial was not designed to statistically compare those 2 arms. The purpose of having 2 arms was to choose the winner, to choose the arm that has the best efficacy and to move forward with an approval.

Patients who were enrolled in the ALTA study had a performance status of 0 to 2. Prior chemotherapy was allowed, but prior second-generation ALK inhibitors were prohibited. The median follow-up of the study was 9 months. In the ALTA study, the 180-mg arm was a winner in pretty much every category. It showed a higher response compared to the 90-mg arm. It showed a higher progression-free survival of 15.6 months compared to about 9 months on the 90-mg arm. It showed higher CNS response and higher intracranial progression-free survival. Toxicity was slightly higher in the 180-mg arm, but toxicities were manageable and dose discontinuations were infrequent. In the ALTA study, nausea and diarrhea were reported in approximately 30% of patients, and this was all grades of nausea and diarrhea. There were no cases of grade 3 diarrhea, and only 1% of patients had a grade 3 nausea.

With brigatinib, there are a couple of other side effects we need to be aware of. Brigatinib can cause elevation of CPK, creatinine phosphokinase, which can be found through a blood test. About 17% of patients who were treated with brigatinib developed hypertension, and you might want to make sure you follow up on the patient’s blood pressure. Some patients require starting antihypertensive medication.

There is also a very unusual side effect that I would like to concentrate more on, which is called early onset pulmonary events. About 12% of the patients who were treated in arm B, which was the 90-mg arm that was then escalated to 180 mg, developed shortness of breath. Usually that shortness of breath happens at about day number 2. It is reversible with discontinuation of the drug. The majority of patients have only mild shortness of breath. The grade 3 early onset pulmonary events only were reported in about 3% of the patients. So, it is important to be aware of early onset pulmonary events. But it would not deter me from starting brigatinib, because the event is reversible and easily manageable.

We have gone a very long way for our patients with non—small cell lung cancer. I think it is very important to not forget to use molecular testing in our patients. Make sure that, at the minimum at least,EGFR,ALK,ROS, andBRAFare included in your panel. I am a big proponent of next-generation sequencing because it can discover other molecular abnormalities. We just had an excellent presentation of one of the RET inhibitors, which showed a 77% response rate in patients withRET-mutant non—small cell lung cancer, and that underscores our need to look for those mutations, because I don’t think we can afford not offering our patients drugs that have such high response rates.

Transcript edited for clarity.

Case: A 50-Year-Old Woman WithALK-Rearranged NSCLC

• A 50-year-old woman first presented with symptoms of dyspnea, persistent cough with bloody sputum, and intermittent right-sided chest pain
• Relevant PMH:
  • Nonsmoker, had childhood exposure to second-hand smoke
  • No history or presence of pneumonia or bronchitis
  • No history of diabetes, cardiovascular disease, or renal disease
• Diagnostic workup:
  • CT of the chest showed right lung mass
  • Biopsy confirmed NSCLC (adenocarcinoma) in right lung
  • MRI showed scattered small brain lesions. Patient is asymptomatic
  • Molecular testing:
    • EGFR and KRASWT
    • IHC:ALK-rearrangement
• Treatment: started on crizotinib; achieved a confirmed partial response including CNS response
• At 12-month follow-up, disease progression seen in the right lung mass, with 2 new liver lesions and progression in the brain
  • Mutation analysis;ALK I1171Nresistance mutation
• She was started on brigatinib 90 mg once daily and tolerated the dose well; after 1 week, her dose was increased to 180 mg once daily (2 90-mg tablets)
  • Had some mild nausea and diarrhea, but continued treatment
  • Achieved partial response, including reduction in CNS and liver lesions
  • At 15-month follow-up, now with stable disease