Resistance Mechanisms in ALK-Rearranged NSCLC

Mohammad Jahanzeb, MD:This patient responded to alectinib, which you expect 70% to 80% of patients to do, but the duration of response, or the progression-free survival was much shorter than 34 months—9 months. I think this patient did not do as well on alectinib.

Resistance to these drugs is what frustrates us all. Eventually resistance develops, and we are trying to keep these patients from getting new chemotherapy by changing drugs. But it’s not a simple story likeEGFR, where 50% to 60% of patients that haveT790Mmutation. We have a drug, osimertinib, approved for that, and osimertinib is first line. Here there’s a whole potpourri ofALKalterations. It’s not just 1 major mutation. There are lots of mutations. And besides those mutations, there are other mechanisms of resistance, of amplifications, or bypass pathway activation, etc.

I think it’s imperative to do a biopsy or at least a liquid biopsy—a blood test—to see what type of resistance mechanism has emerged. There are different mechanisms. When you see a patient progressing on crizotinib, that’s a different spectrum from if the patient progresses on a second-generation ALK inhibitor. And 1 of the problematic mutations after progression on second-line therapy can be a 1202R mutation, which is covered by brigatinib at the dose of 180 mg. It is also covered by lorlatinib, the fifth approval that we got in subsequent-line therapy. But it’s not covered for alectinib, for example. So one has to be cognizant of what mutation it is, which drugs cover it, and which drugs don’t.

In terms of what we recommend after progression: biopsy, or at least a liquid biopsy. And if that’s negative, do not assume that there is no nonmechanism. Then go to a tissue biopsy in every case if possible.

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