Treatment Options for ALK-Rearranged NSCLC

Lyudmila A. Bazhenova, MD:Before we had access to ALK tyrosine kinase inhibitors,ALKmutation signified a worse prognosis. We have several studies published looking at response rates to chemotherapy comparing response rates to chemotherapy in patients withALKrearrangements and withoutALKrearrangements, and patients withALKrearrangements respond to chemotherapy less well, with the exception of pemetrexed. We have data published looking at 5 years’ progression or recurrence-free risk for patients withALKrearrangements, and we know thatALK-rearranged patients are twice as likely to progress or recur 5 years from the time of the diagnosis.

Currently in the United States, for patients with newly diagnosed metastaticALK-rearranged lung cancer, we have 3 drugs approved: crizotinib, which was the first drug approved; ceritinib; as well as alectinib. Two of those, crizotinib and ceritinib, had first-line studies comparing them to chemotherapy. Alectinib is the only ALK inhibitor that has a first-line trial comparing it to another ALK inhibitor, which is crizotinib. My personal choice is alectinib because it has been shown to result in the longest ever reported progression-free survival. The data, which will be updated this ASCO meeting, now show progression-free survival of alectinib at 34 months. This is actually a remarkable achievement. Imagine that we have patients with stage 4 lung cancer who are still receiving first-line therapy 3 years after the time of their diagnosis. The major breakthrough in this setting is approval of alectinib in the first line and the significant efficacy of alectinib, both systemically as well as in the CNS.

This patient’s response to crizotinib was as expected. Based on PROFILE 1014, we know that response to crizotinib ranges between 70% to 80%. The progression-free survival has been reported at about 10.9 months. The fact that this patient progressed at 12 months of therapy is something that we would expect. Unfortunately, older patients will develop resistance to ALK inhibitors.

Post progression biopsies have been done in patients who develop resistance to crizotinib. What we learned from that is about a third of the patients will develop resistance in the ALK domain. We call them ALK-dependent resistant. A majority of those patients develop a secondary mutation in the ALK domain, and this patient has mutation 1171. Based on the preclinical data, we know that this mutation predicts resistance to alectinib. Brigatinib, however, covers that mutation completely. Another important mutation that is emerging to be pan-resistant is 1202R, and brigatinib is another drug that has activity against that mutation: Neither ceritinib nor alectinib is active against 1202R.

In the patient who has progressed post crizotinib, doing a post progression biopsy could be recommended. If you have any information about a specific point mutation in the ALK domain, then you can refer yourself to published information looking at sensitivity of second-generation ALK inhibitors against the specific mutation.

We do have approved drugs, as well as upcoming drugs, that cover a majority of the resistance mutations. My personal feeling is that if you decide to use brigatinib, which covers the majority of the resistance mutations, you might forgo the biopsy. But if you are choosing between ceritinib and alectinib, I think it is important to know what resistance mutation to crizotinib is covered by the drug that you choose.

Another important point of information is the fact that you do not have to have a resistant mutation in the ALK domain to respond to second-generation ALK inhibitors. If you did the post progression biopsy and found that the patient had a wild-type, meaning nonmutated but still rearranged,ALK, you still have a possibility of this patient responding to second-generation ALK inhibitors. If one looks at the reported responses for second-generation ALK inhibitors, they range anywhere between 60% to 70%. ButALKpoint mutations only happen in about 30% of the patients, so the rest of the responders do not have anALKpoint mutation.

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