Challenges in ALK-Positive NSCLC Management

Web Exclusives - Conference Correspondent

Chicago, IL—The anaplastic lymphoma kinase (ALK) mutation is a target for tyrosine kinase therapies in several cancers, including non–small-cell lung cancer (NSCLC). Since 2011, several ALK inhibitors have been approved, and more are in the pipeline, but many questions remain for managing patients with ALK-positive NSCLC. Jim Koeller, MS, Professor, Center for Pharmacoeconomic Studies, College of Pharmacy, the University of Texas at Austin, discussed current challenges in the management of patients with ALK-positive NSCLC at the 2016 Annual Hematology/Oncology Pharmacy Association (HOPA) Oncology Pharmacy Practice Management Program.

Between 2% and 8% of NSCLC tumors are ALK-positive, representing more than 30,000 new cases of ALK-positive NSCLC worldwide every year.

“This is a relatively small percentage, but when you’re dealing with the entire lung cancer population, 5% can add up pretty quickly,” said Mr Koeller. In NSCLC, ALK is rearranged to create the EML4-ALK oncogene, which leads to increased growth of cancer cells.

“As with other diseases, this typically translates to a worse prognosis for patients,” he said. Before the introduction of targeted therapies, patients with NSCLC and the ALK mutation had double the risk for disease progression or recurrence within 5 years of diagnosis compared with patients without ALK mutation.

Testing for ALK Mutation

Current National Comprehensive Cancer Network guidelines recommend testing for ALK mutation in patients with NSCLC. The ALK mutation is diagnosed by molecular profiling of a tumor sample; clinical characteristics alone cannot identify patients with ALK-positive NSCLC.

“You need to do a genetic test, and you need to have tissue, which makes testing a little more difficult. But there are some clinical indicators that can lead you to the promised land,” Mr Koeller said.

Most ALK-positive NSCLCs are adenocarcinomas and are not typically associated with smoking, and patients are often in their 50s (median age, 52 years).

Several diagnostic platforms have been developed to detect ALK-positive disease. A fluorescence in situ hybridization probe is used most often, followed by an immunohistochemistry assay. Next-generation sequencing and reverse transcriptase polymerase chain reaction tests can also identify patients for ALK-targeted therapy, although these therapies have not been granted FDA approval.

“In the diagnostic phase, there should be discussions in institutions with pharmacists included,” Mr Koeller told The Oncology Pharmacist (TOP). “They need to talk about the appropriate genetic test, and which markers are known to identify with the disease.” The pharmacist should then be involved in treatment decisions based on test results.

“There’s a reason to identify genetic markers, because these patients, on the right drug, can be effectively treated with very reasonable oral therapy, and can survive months to years. That’s a good thing,” he told TOP.

Current Treatment Guidelines

In 2011, crizotinib (Xalkori) was approved as the first ALK inhibitor. The National Comprehensive Cancer Network guidelines recommend ALK inhibition with crizotinib for the first-line treatment of patients with advanced-stage or metastatic ALK-positive NSCLC, but Mr Koeller does not recommend interrupting treatment when the ALK rearrangement is discovered during first-line chemotherapy.

“I’m not sure it’s wise to stop therapy if a patient with stable disease is responding to treatment. I would continue until they no longer respond, then switch to the appropriate agent. But this timeline is not being met appropriately yet,” he said.

Mr Koeller also emphasized the importance of pharmacists in delivering targeted therapies.

“Drug management—compliance, adherence, monitoring, tracking, changing dosing—all of these are big issues,” he told TOP. “We have to get better at managing these agents, so I think there are a lot of places for pharmacists to be involved, especially in lung cancer.”

But even with targeted therapies, cancer cells can develop resistance, and acquired resistance can be a major clinical challenge. Multiple mutations can confer resistance to ALK inhibitors, and these mutations may be heterogeneous, underlining the need for pathologists to collect as much tissue as possible for molecular testing.

Remaining Challenges

The central nervous system is a frequent site for ALK-positive NSCLC progression. According to Mr Koeller, brain metastases are associated with a poor prognosis, and some of these metastases can recur relatively quickly, creating a burden in the patient population with ALK-positive NSCLC.

“Once you get brain metastases you see pharmacy costs, emergency room costs, outpatient and inpatient treatment costs, and other medical service costs skyrocket,” he said.

The mechanisms of resistance in ALK-positive NSCLC brain metastases remain elusive. Ideally, future ALK inhibitors will need to penetrate the blood−brain barrier.

According to Mr Koeller, clinicians need a better understanding of optimal strategies for detecting of ALK mutations in patients with NSCLC through multiple genetic tests, individual tests, or a combination.

“One of the issues is trying to get insurers to understand the value of these tests,” he stated. “So we need to get the data out there, especially with the changes to healthcare that are going to force us into more strategized treatment and more cost-effective use of our resources.”

A firmer grasp on the resistance mechanisms and a deeper knowledge of the drivers of disease progression are also needed, he added.

The usefulness of rebiopsy at disease progression is contested, but Mr Koeller told TOP that he strongly encourages making it standard practice to identify the patient’s need for another targeted drug, initiation of chemotherapy, or some other course of treatment.

“There are a lot of reasons why this doesn’t occur—the patient doesn’t want to do it, or the surgeon doesn’t want to go back in—but I think we need to set this up in the pathway as a standard approach. That’s probably the way to move this forward,” he concluded.

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Last modified: February 22, 2023