Available Treatment Options for Relapsed ALK-Rearranged NSCLC

Mohammad Jahanzeb, MD:In terms of what subsequent-line therapies can be used in a patient who progresses on an ALK inhibitor, it’s now relatively easy in the United States to pick 1 of 3 drugs that are in the NCCN [National Comprehensive Cancer Network] Guidelines for first-line therapy. I already said that alectinib and brigatinib have an edge for better CNS [central nervous system] penetration, even though ceritinib penetrates the CNS as well. One would not use crizotinib in the United States because it has a very big delta in terms of its inferiority to the other ALK inhibitors. That’s not really an optimal choice.

After failure on 1 of the newer-generation ALK inhibitors, you would do a biopsy. Then you may look to use the next 1. For example, if you used alectinib, there was 1202R. You know that you can use brigatinib or lorlatinib. In terms of toxicity profile, brigatinib would then be selected over lorlatinib. That would be the optimal choice. When that fails, maybe you’ll try lorlatinib. Ultimately, resistance develops to all of them. Then you go back to a platinum-based doublet therapy, which still works in these patients.

When we think about the choice of brigatinib after alectinib in this patient and try to look for evidence, there is limited evidence. We know it’s a rare disease and patients get parceled out into smaller and smaller subsets. When you look at the abstract from last year’s American Society of Clinical Oncology Annual Meeting, Dr Thomas E. Stinchcombe [of the Duke Cancer Institute] had an abstract on the use of brigatinib and patients who had failed on a second-line or second-generation ALK inhibitor. In a group of 19 available patients, there were 8 responders. Obviously, you don’t expect a very high response rate, but I think these are small numbers. Eight of 19 is a respectable proportion of patients. At least it gives biological evidence of activity in the clinical setting. I think that bears out the choice that was made to give the patient brigatinib.

There was another publication by Dr Karen Reckamp [of City of Hope hospital] that really is a cross-trial comparison. We always say we don’t do cross-trial comparisons, but honestly, in clinic we do it all day long, every day when we have a patient in front of us. In this trial in which they used patient-level data from ALTA but also used trial-level data from publications for the other ALK inhibitors, she concluded that on the basis of efficacy versus toxicity, brigatinib is superior. That was the author’s conclusion.

Transcript edited for clarity.

Case: A 61-Year-Old Man WithALK-Rearranged NSCLC

• A 61-year-old man presented with recent onset shortness of breath and swelling above left clavicle.
• Relevant PMH:
  • Nonsmoker, no previous CV- or pulmonary-related complications
• PE: Lungs, right-sided wheezing on auscultation; left supraclavicular lymphadenopathy, palpable
• Diagnostic workup:
  • Labs: WNL
  • Lymph node biopsy showed adenocarcinoma
  • CT CAP showed a 2.5-cm solid pulmonary lesion in the left inferior lobe and multiple liver lesions
  • CT‐guided core needle biopsy of the lung lesion revealed lung adenocarcinoma
  • Molecular testing:
    • EGFR, BRAF, KRAS, MET, RET, NTRKwild-type
    • IHC;ALK-rearrangement
    • PD-L1 TPS, 0%
  • Contrast‐enhanced MRI of the head showed multiple brain metastases
• Treatment:
  • Started on alectinib 600 mg BID; achieved a partial response including regression of CNS disease
  • Patient developed grade 3 myalgia; dose reduced to 450 mg BID, sustained at grade 2
• Imaging at 9 months showed disease progression in the lung mass and liver; stable CNS disease
  • Lung biopsy, mutation analysis;ALKG1202R
• He 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)
  • Partial response with significant shrinkage in lung, liver, and CNS lesions