Deciding on Treatment for Relapsed ALK-Mutant NSCLC

Lyudmila A. Bazhenova, MD:When we decide which second-generation ALK inhibitors to use, since we do not have any randomized clinical trials with patients who progressed on crizotinib comparing ceritinib versus alectinib versus brigatinib, we have to use other factors. One can look at toxicity. As we mentioned, ceritinib causes more GI toxicity, alectinib causes more muscle toxicity. Cost is important, if there is a differential cost to the patient based on the ALK inhibitor. Efficacy wise, it is hard to say that one of the second-generation ALK inhibitors is better than the other without having direct head-to-head data, so we have to be forced into doing a cross-trial comparison.

When you look at the performance of ceritinib post crizotinib, and when you look at the performance of alectinib post crizotinib, and then follow that with the performance of brigatinib post-crizotinib, brigatinib, so far, has the longest reported PFS. So, compared to ceritinib and alectinib, where PFS is in the order of 9 to 11 to 12 months, with a phase I brigatinib study the updated progression-free survival at ASCO was 16.3 months. And from the ALTA study, which is a phase II brigatinib study, the progression-free survival was over 15 months. So, any of the second-generation ALK inhibitors will be a correct answer. My personal preference is brigatinib, because this is the drug with the longest reported progression-free survival.

I think it’s also important that, when we decide to choose which second-generation ALK inhibitor to use, we also look into the performance of those drugs in the CNS. We know that for patients with stage 4 lung cancer with anALKfusion gene, disease has a propensity of metastasizing to the brain. We also know that the ability of crizotinib to control the brain is not as good as the ability of ceritinib, alectinib, or brigatinib to control the brain. We have discussed the ALEX study, where we looked at direct head-to head comparison of crizotinib versus alectinib. In the ALEX study, patients who received alectinib has less likelihood of recurrences in the brain than patients who received crizotinib. We have very good evidence that ceritinib, as well as brigatinib, also have very good CNS penetration and CNS control. For some of your patients, the schedule of administration might be important. Ceritinib and alectinib are twice-a-day medications, while brigatinib is once-a-day. So, there are some patients who are having a hard time with compliance, where you might decide to use one drug versus another.

For our patients withALK, ceritinib has been approved in May of 2017. Alectinib currently does not have an approval, but based on the results of the ALEX data, it has made it on to NCCN guidelines. That opens a completely new territory for us, because up until this point, we studied how ceritinib works after crizotinib, how alectinib works after crizotinib, and how brigatinib works after crizotinib. We really don’t have any data on how ceritinib works after alectinib, or how brigatinib works after alectinib. There are some emerging data on efficacy of lorlatinib, which is a third-generation ALK inhibitor, which is being investigated with how it works after alectinib. But I think we need to generate more data to understand what to do if you choose alectinib for your patient, and what would be the right second ALK inhibitor to use once the patient progresses on alectinib.

Brigatinib has been investigated in a phase I trial as well as in a phase II trial. The phase II trial is called ALTA. In the phase II trial, patients were randomized to brigatinib at 90 mg versus brigatinib at a lead-in dose of 90 mg followed by an escalation to 180 mg. It was not a comparison to chemotherapy or other ALK inhibitors. Brigatinib showed a very high response rate, and I already mentioned that for the ALTA study, progression-free survival for the patients who have failed crizotinib was over 15 months. One more interesting thing about brigatinib is that, in the preclinical data using cell cultures, we know brigatinib covers the majority of theALK-resistant mutations, and that would be one more rationale to consider with brigatinib in addition to longest reported progression-free survival for patients.

Transcript edited for clarity.

ALK-Rearranged NSCLC Progressing on Crizotinib

August 2016

• A 59-year-old Caucasian male presented with symptoms of cough and dyspnea
• PMH: hypertension managed on a calcium channel blocker; osteoarthritis
• Former smoker, 10 pack-years
• CT of the chest and abdomen revealed a 6.0 cm spiculated mass in the left lower lobe, a loculated pleural effusion in the right hemithorax, and diffuse liver nodules
• Bronchoscopy and transbronchial lung biopsy revealed a poorly differentiated adenocarcinoma of the lung. Cytopathologic examination of pleural fluid was positive for malignancy
  • Molecular testing:
    • IHC: positive forALKgene rearrangement
    • NGS: negative forEGFR, ROS1, BRAF
    • IHC: PD-L1 expression in 0% of cells
  • PET/CT showed¹⁸F-FDG uptake in the left lung mass, right pleura, and liver
  • Brain MRI, negative for intracranial metastases
• The patient was started on therapy with crizotinib
• Imaging at 3 and 6 months showed continued shrinkage of the lung mass and liver lesions and resolution of pleural metastases
• Imaging at 9 months showed a small increase (2 mm) in the lung mass

June 2017

• After 13 months on crizotinib, the patient reported mild dyspnea and weight loss
• CT of the chest and abdomen showed increased size of 1.5 cm in the pulmonary mass, several new small lesions in the right lower lobe (<1 cm), and 2 left-sided adrenal masses, measuring 3.0 cm and 3.2 cm
• Brain MRI, negative for intracranial metastases