The Future of ALK-Rearranged NSCLC

Mohammad Jahanzeb, MD:When we think of future directions forALK, 1 thing we keep in mind is that most community medical oncologists who are not focused on lung cancer will probably see fewer patients withALK-positive lung cancer, where there are already pills available in the market to treat. The experience is not going to be broad and vast. We constantly try to further the field to see what’s next and how to best sequence these drugs. Sequencing these drugs is going to be a huge issue. You have so many options, and patients will eventually become resistant to 1 or the other or the next.

There’s an NCI [National Cancer Institute]—NRG [Oncology] ALK Master Protocol that actually relies on assessment of resistance mechanisms or rebiopsy and mutation testing. Patients are sent to the right pathway to pick the drug that does cover that mechanism of resistance. Since there’s overlap, there are multiple options at these decision points. So the trial gives us at least a repository of data with tissue available to analyze, which will expand our understanding of how to further develop these compounds or how to combine them. So combinations are another avenue. Unfortunately the data that we have point to immunotherapy being relatively useless. We have to find nonimmunotherapy partners and see how maybe they could be integrated in some fashion with chemotherapy drugs with other new emerging compounds. That’s going to be the direction we’ll go in the future.

When we think of immunotherapy, for cancers that have developed under carcinogenic pressure—like melanoma under ultraviolet radiation, or toxic substances and tobacco smoking, for which you’ve seen cancers of the head and neck, esophagus, lung, bladder, etc—we expect accumulations of a lot of mutations, a high tumor mutation burden, and a separate biomarker from PD-L1 [programmed death-ligand 1]. We tend to see immunotherapy as more effective. For cancers that are otherwise pristine but have 1 thing wrong with them, there’s 1 pathway. It’s likeEGFRorALK. They’re not immunogenically as distinct from the rest of the body. So immunotherapy tends to be less effective in those tumors.

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