Treatment Courses for ALK Resistance in NSCLC

At the virtual 2020 Personalized Therapies in Thoracic Oncology meeting, Jonathan Goldman, MD, provided an overview of how to manage patients with ALK-resistance in non-small-cell lung cancer (NSCLC).

Dr Goldman addressed clinical and molecular factors in assessing resistance in NSCLC as well as choosing the optimal agent to treat resistance.

Many trials have looked at this question, he stated, beginning with sequential TKI therapy soon after crizotinib and the development of resistance, looking at agents such as alectinib and brigatinib with impressive response rates and duration of response, and ceritinib showing some activity.

After second generation drugs, alectinib or brigatinib, lorlatinib demonstrated a meaningful response rate, ceritinib again demonstrating less activity. Less data is available for chemotherapy following ALK inhibitors for patients.

The most recent data available in the chemotherapy space is the Impower150 trial looking at carboplatin, paclitaxel, bevacizumab and atezolizumab “which included a small number of ALK+ patients making up this large overall postive trial,” noted Dr Goldman.

Since different TKIs lead to an assortment of resistance mechanisms, often the first step is a biopsy. Plasma biopsy may be able to show more mutations than tissue biopsy but Dr Goldman explained tumor biopsies and liquid biopsies (cell-free and circulating tumor DNA) all play a role in determining if continuation with locally ablative therapy is appropriate, it’s time to switch to a new TKI, or its time to switch to chemotherapy with or without immunotherapy or continuing the TKI therapy.

Dr Goldman highlighted the performance status factors to look for in a clinical assessment of patients as well as types of progression to consider when determining the right next step in treatment.

The presentation shared tables of different resistance mutations that emerge in ALK inhibitors, benefits of plasma testing, examples of patients’ flowcharts of ALK mutations, NCCN guidelines, and treatments of choice by mutation.

Dr Goldman walked listeners through oligoprogression and treatment choices as well as multi-site progression possibilities and subsequent treatment choices.

“You’ll see that lorlatinib is often one of your options but I do find it to be one of the TKIs for ALK that has more toxicity. Therefore, if a drug like brigatinib looks like it may also be effective, I’m often choosing that preferentially,” Dr Goldman highlighted for viewers.

More agents to come mentioned included entractinib, ensartinib, belizatinib and a few other TKIs undergoing further study, allosteric inhibitors, and new combinations of TKIs with bevacizumab and co-inhibition with other agents are being further evaluated.—Kaitlyn Manasterski

Goldman J. How to handle ALK resistance. Presented at: Personalized Therapies in Thoracic Oncology; November 20-21, 2020; virtual.