Contemporary Care for a Patient With Non-Small Cell Lung Cancer and ALK Fusion

Corey Langer, MD, describes the treatment course for an 82-year-old never-smoker patient with advanced non-small cell lung cancer harboring an ALK fusion.

Dr Langer highlights the important of using the appropriate tyrosine kinase inhibitor (TKI) when a patient with NSCLC is positive for oncogenic drivers. He also weighs the decision between two TKIs in this case, alectinib or lorlatinib.

Transcript:

Hello, my name's Corey Langer, professor of Medicine Pearlman School of Medicine, University of Pennsylvania, and I'm the Director of Thoracic Oncology at the Abramson Cancer Center, where I've had the privilege of working for the past 17 years and before that 22 years at Fox Chase Cancer Center. So I am a card-carrying member of the thoracic cognoscente.

I have a case that I'd like to discuss that I think brings up 2 very important points. Number one, that age is no impediment to treatment, particularly when it comes to targeted therapy. And also, that liquid biopsy can sometimes substitute or complement our therapeutic decision making.

The patient is an 82-year-old gentleman, never-smoker, with a history of atrial fibrillation on Eliquis [apixaban] who presented in November of 2022, during the height of the pandemic, with shortness of breath on exertion and elevated liver function tests. He underwent a CAT scan of the chest, abdomen, and pelvis, which showed multiple bilateral renal masses that were highly suspicious for metastatic disease and a solitary liver lesion. CT of the chest in early November of that year confirmed a bulky right upper lobe mass with extensive right hilar and mediastinal adenopathy bronchitis. In the middle of November, confirmed adenocarcinoma with mucinous features and his PD-L1 was 80%; brain MRI was negative.

At this point, he was staged as stage 4, on the basis of kidney and liver metastasis and with the high PD-L1, the inclination by outside physicians was to implement a checkpoint inhibitor, specifically pembrolizumab. But because he was the never-smoker and had adenocarcinoma histology, it was imperative, particularly in the absence of significant symptoms, that we await the testing for molecular markers.

And intriguingly, while we awaited the testing for next generation sequencing, a liquid biopsy actually returned positive for ALK fusion. As we're well aware, liquid biopsy specificity is quite good on the order of 95% to 98%. If it's positive on liquid biopsy, it's real, it's not an artifact. Sensitivity is a bit less, probably on the order of 65% to 75%, and it's directly proportional to the tumor burden, also the presence or absence of disease outside the chest.

The question here, what is the next step, the best therapeutic approach for a gentleman this age with this sort of background? Is it pembrolizumab? Is it crizotinib, in light of the ALK positivity? Would you consider combining pembrolizumab, based on the high PD-L1 with either a second-generation TKI [tyrosine kinase inhibitor] like alectinib, or a third-generation ALK TKI like lorlatinib? Would you do either of those agents alone?

The answer is fairly complex. For patients with metastatic non-small cell lung cancer with oncogenic drivers, the appropriate tyrosine kinase inhibitor, TKI, is clearly preferred over checkpoint inhibitor. Even in patients with relatively high levels of PD-L1, checkpoint inhibitors, when they are administered in those with oncogenic drivers, are typically reserved for the third- or fourth-line setting. There's relatively little activity, particularly in patients whose tumors harbor EGFR mutations or ALK fusions or ROS or RET fusions. Moreover, there's been very little correlation between PD-L1 levels and the activity of checkpoint inhibitors in patients who do have these molecular oncogenic drivers. In addition, in the argument against choice C, early data suggested heightened toxicity when tyrosine kinase inhibitors or TKIs are combined with checkpoint inhibitors.

When it comes to the actual TKI, both alectinib in the ALEX trial and lorlatinib in the CROWN trial have clearly yielded superior activity compared to the historic control arm of crizotinib, with respect to both progression-free survival and CNS [central nervous system] penetrance. Many these days prefer lorlatinib, based on 5-year progression-free survival rates of 60% or higher, and amazing levels of CNS penetrance: CNS progression-free survival at 5 years of over 90%.

But lorlatinib is much more toxic. It can cause elevations in cholesterol and lipids. It can cause significant amounts of peripheral edema. And most concerningly, particularly for an elderly gentleman, it can cause cognitive and sometimes neuropsychiatric changes, as well as peripheral neuropathy.

From the standpoint of toxicity, alectinib in my opinion, is superior to lorlatinib and probably preferred in elderly individuals with some comorbidities. Unfortunately, at least to date, alectinib and lorlatinib have not yet been compared head-to-head in metastatic non-small cell patients with ALK fusion.

In this regard, patient started alectinib, he was fully functional. His dyspnea on exertion disappeared quite quickly and he has had minimal toxicity to date, occasional calf cramps. His performance status at this point is 0, totally asymptomatic, and his response has continued for at least 30 months and counting. His quality of life has been completely preserved and he is needless to say, quite grateful, particularly when handed what he believed to be an automatic death sentence at diagnosis with metastatic lung cancer to the kidneys.

Historically, if we go back in time 20 or 25 years, someone with this diagnosis with stage 4 disease, particularly in this age range, would expect to have a median survival of no better than 9 to 12 months. The recognition of oncogenic drivers and the advent of appropriate targeted therapy for these drivers has really altered prognosis in both quality and quantity of life.

Source:

Peters S, Camidge DR, Shaw AT, et al. Alectinib versus crizotinib in untreated ALK-positive non-small-cell lung cancer. N Engl J Med. 2017;377(9). doi:10.1056/NEJMoa1704795

T Mok, Cambridge DR, Gadgeel SM, et al. Updated overall survival and final progression-free survival data for patients with treatment-naive advanced ALK-positive non-small-cell lung cancer in the ALEX trial. Ann Oncol. 2020;31(8):1056-1064. doi: 10.1016/j.annonc.2020.04.473

Shaw AT, Bauer TM, de Marinis F, et al. First-line lorlatinib or crizotinib in advanced ALK-positive lung cancer. N Engl J Med. 2020;383(21):2018+2029. doi: 10.1056/NEJMoa2027187

Solomon BJ, Liu G, Felip E, et al. Lorlatinib versus crizotinib in patients with advanced ALK-positive non-small cell lung cancer: 5-year outcomes from the phase III CROWN study. J Clin Oncol. 2024;42(29). doi: 10.1200/JCO.24.00581