Therapeutic Approaches for Relapsed ALK-Rearranged NSCLC

Lyudmila A. Bazhenova, MD:This patient did very well until June of 2017, when he developed some shortness of breath. He was also due for a surveillance CT scan, and, unfortunately, the surveillance CT scan showed progression. The patient had new tumors in his adrenal glands, and he had enlargement of the tumors in his lung. He had a brain MRI, which actually would be very appropriate to do when you are evaluating the progression of patients who have been on crizotinib, because crizotinib does not cover the brain very well. The brain MRI was negative for metastasis.

We are very lucky that primary resistance to ALK inhibitors is extremely rare. If you look at all the drugs that we’ve discussed today, which are crizotinib, alectinib, and ceritinib, the incidence of a patient developing primary resistance is in the order of 6% to 8%. When one tries to evaluate what the mechanism of that resistance is, what we have seen is an unusual fusion partner. In the majority ofALKfusion patients,ALKis fused to something called anEML4. But, if you have an unusual fusion partner, that leads to potential resistance. We also see additional mutations: People have describedKITmutations,PTENmutations, andmTORmutations as mechanisms of primary resistance.

Secondary resistance is much more common. I think the chance of a patient developing secondary resistance to an ALK inhibitor is 100%. If you look at reported progression-free survival for crizotinib, based on either the ALEX study or PROFILE 1014, median progression-free survival is about 11 months. So, we know that at some point the patient will develop resistance.

We are learning more and more about the mechanisms of resistance to ALK inhibitors, and we divide those resistances into 2 types. We call 1 on-target ALK resistance, where you can either develop a secondary mutation in the ALK kinase domain, or you can develop an ALK amplification, or so-called off-target ALK resistance, where a tumor can develop additional bypass pathways that weren’t present at the time of the original diagnosis. And many bypass pathways have been described:EGFR,FGFR, andBRAF. What’s interesting, however, is that the response of a crizotinib-failing patient to a second-generation ALK inhibitor does not depend on the type of the resistance. So, patients who do not have an on-target ALK resistance, meaning they develop a bypass pathway, can still respond to second-generation ALK inhibitors.

At this point, it is not considered standard to rebiopsy the patient to determine the mechanism of resistance. We are still learning the types of resistance we have. What we know is that for the on-target resistance, when you have a secondary mutation in ALK kinase domain, many mutations have been described. And there are some mutations that tell us that ceritinib will not be a good answer for the patient because that mutation is resistant to ceritinib, but it could be sensitive to alectinib. In my practice, I do post-progression biopsies. We do not have any trials telling us what’s the right way of sequencing ALK inhibitors, but if I did the biopsy and I found a mutation that is predicted to be resistant to ceritinib, it behooves me not to use ceritinib. In that situation, I would prefer to use alectinib.

With liquid biopsies for patients withALK-fused cancer, it is a little bit harder to find theALKmutation than, for example,EGFRmutations. We have reported at ASCO 2017 our experience with brigatinib and using a liquid biopsy from the company called Resolution Diagnostics. We took patients who were known to have anALKfusion gene, and then did plasma testing using their proprietary assay, and we found that only about 57% of the patients with a known tissueALKfusion gene will have the ALK fusion plasma. So, if you find ALK fusion in plasma in liquid biopsy, it is helpful. But, if you don’t find it, it doesn’t mean that it’s not existing in the tissue. It is important to follow all your negative liquid biopsies with next-generation sequencing.

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