With Limited Progression, Maintaining TKI Regimen Often Optimal Approach in Lung Cancer

Gregory J. Riely, MD, PhD

How should oncologists respond when initial treatment of EGFR-mutant or ALK-positive lung cancer with a tyrosine kinase inhibitor (TKI) no longer prevents all disease progression?

Staying with the same TKI regimen is often the best response because progression by some measures does not mean that the therapy is not still working, said Gregory J. Riely, MD, PhD, at the 9th Annual New York Lung Cancer Symposium.

In his discussion, Riely, who is vice chair of the Clinical Trials Office in the Department of Medicine at Memorial Sloan Kettering Cancer Center, explained when to leave treatment protocols unchanged and what to do when altering treatment becomes necessary.

“If there’s asymptomatic progression at multiple sites, I generally do nothing,” Riely said. “If we let things go, we can keep people alive and well for a year or more after disease reaches the RECIST definition for progression.”

The strategy works, Riely said, because disease that is technically “progressing” is often progressing very slowly and not putting the patient in any distress. Indeed, a study of lung cancer patients receiving the TKI erlotinib (Tarceva) found that median progression-free survival (PFS) as defined by their physicians was more than 3 months longer than median PFS as defined by RECIST.

Riely decides when to adjust protocols and when to leave treatment unchanged by evaluating each patient at the first sign of progression. These assessments focus mostly on the speed of tumor growth, the number of new lesions (if any), and how patients feel.

When this evaluation demonstrates the need for something more than watch-and-wait, Riely still resists the urge to abandon erlotinib (or whatever other treatment has been working). Instead, when he finds a small number of new lesions, he often advocates some form of local therapy, even when those lesions aren’t producing symptoms.

Preliminary research suggests that a wide variety of local therapies can provide significant benefits to patients with EGFR-mutant lung cancer that has begun to acquire resistance to erlotinib. A study of 18 patients who underwent seven different types of treatment, for example, found that the median time to progression after local treatment was 10 months, and that the median overall survival after local therapy was 41 months.

Perhaps more importantly, local treatment of lesions that demonstrated resistance to erlotinib allowed patient to receive a much greater benefit from the drug.

“The median time after local treatment until doctors had to start giving patients a new systemic therapy was nearly 2 years,” Riely said. “That definitely shows some value in the approach.”

The appropriate form of local therapy will naturally vary with the location and the nature of each patient’s lesion or lesions. Procedures in the studies that Riely cited included adrenalectomy, radiation therapy, lobectomy, and radiofrequency ablation.

Physicians who undertake such local treatments might be tempted to stop using the primary treatment, figuring that progression indicated resistance and rendered the drug useless, but Riely urged his audience to view local treatments as a complement to treatments such as erlotinib rather than a substitute for them.

“If you ignore the rest of the body by dropping erlotinib, you risk disease flare,” he said. “The local treatment is, by definition, localized to individual lesions that have become resistant. You have to continue to treat the rest of the body.”

Research has yet to demonstrate exactly which patients will benefit from what sort of local therapy, but Riely follows some general rules of thumb in his practice.

Among people with ALK-positive or EGFR-mutant metastatic non—small cell lung cancer, he looks for patients who tolerate whatever TKI they’re using well enough to withstand additional treatment. He also limits the practice to patients with oligoprogressive disease, defined as central nervous system progression (without leptomeningeal disease) and/or progression at up to four non-CNS sites.

If progression occurs at more than five sites, or if it appears unlikely to respond to local treatment, Riely generally advocates some change to the patient’s overall treatment.

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