Emerging Therapies and Combinations for ALK-Mutant NSCLC

Lyudmila A. Bazhenova, MD:We all are aware that immunotherapy has been a major breakthrough in lung cancer treatment for stage 4 lung cancer. However, what we’re also learning is that immunotherapy is not as effective for patients withALKmutations as well asEGFRmutations. So, outside of the clinical trial, I will not be using immunotherapy up front for patients withALK-fused genes. I might consider using it down the line, after I go through all my desired ALK inhibitors and probably give them a platinum-based doublet. Because, we know pemetrexed works very well forALK-mutant lung cancer patients. Maybe somewhere down the line we can use immunotherapy, but at this point the data are underwhelming for the efficacy of immunotherapy inALK-fused lung cancers. Currently, we have several studies looking at the efficacy of immunotherapy in combination with ALK inhibitors. Those studies have not been showing us any data yet, and I think eventually we will learn if adding immunotherapy to, let’s say, crizotinib at the time of the patient diagnosis will make a difference.

Lorlatinib is a third-generation ALK inhibitor that is currently being investigated for patients withALK-fused stage 4 lung cancer who have failed 1 or 2 ALK inhibitors. Preliminary data look certainly interesting, but we are noticing that efficacy of lorlatinib is better if the patient had 1 ALK inhibitor versus 2 ALK inhibitors versus 3 ALK inhibitors. Lorlatinib is an interesting drug. There is 1 very resistant mutation in theALKkinase domain called 1202R. Ceritinib doesn’t cover that mutation. Alectinib doesn’t cover that mutation. There are some case reports of patients with that mutation responding to brigatinib. But one benefit of lorlatinib is that it covers that resistant mutation. This resistance mutation is not really that frequent, but there is certainly some preclinical rationale that lorlatinib will be able to salvage some of those patients who develop resistance to crizotinib or to other second-generation drugs based on1202R.

We also see improvement in the management of the patients withROS1-mutant lung cancer. Currently, we have crizotinib, which is approved forROS1-mutant patients, but other drugs such as entrectinib are being investigated for that population. I haven’t seen any data yet, so, at this point, I can’t really say if entrectinib is going to become the next standard of care option for those patients. But, preclinically, entrectinib has very good activity againstROS-mutant cancers.

Today, we covered a lot of very important questions, and for a lot of those questions we do not have an answer. I think the question that we’re all eager to find an answer to is, “What’s the right way of sequencing ALK inhibitors?” It will take some additional trials, and I hope that in the future we will learn what the right thing to do is for our patients. I hope that in the future, we will be able to have more third-generation ALK inhibitors effective against resistant mutations that we’ve discussed today. I strongly support everybody who is listening to me to treat yourALK-mutant patients on trials, because that’s the only way we can get better. That’s the only way we can find answers to questions that we covered today.

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