In the Journals

Resistance to osimertinib for non-small cell lung cancer appears genetically heterogeneous

Geoffrey Oxnard
Geoffrey R. Oxnard

Loss of the EGFR T790M mutation at time of treatment failure with osimertinib appeared associated with the development of a range of competing resistance mechanisms among patients with advanced non-small cell lung cancer, according to findings published in JAMA Oncology.

Thus, there is a need to develop strategies to detect and target multiple coexistent resistance mechanisms to achieve more durable control of drug resistance in EGFR-mutant lung cancer, according to the researchers.

“In patients with EGFR-mutant lung cancer receiving osimertinib [Tagrisso, AstraZeneca] for the EGFR T790M resistance mutation, clinicians need to keep an eye out for early resistance due to emergence of alternate resistance mechanisms,” Geoffrey R. Oxnard, MD, associate professor of medicine at Dana-Farber Cancer Institute and Harvard Medical School, told HemOnc Today. “Such patients could be candidates for combination approaches of osimertinib plus another drug, such as the addition of a MET inhibitor to target MET amplification.”

Widespread use of osimertinib — a third-generation tyrosine kinase inhibitor — has led to a clinical problem of acquired resistance. Targeted treatment approaches are in development to overcome resistance.

Oxnard and colleagues sought to understand clinical and molecular indicators for resistance in a larger cohort, in an effort to determine different molecular mechanisms of resistance and treatment approaches.

Investigators performed next-generation sequencing on tumor biopsies of patients from a multi-institutional cohort (n = 143) and validation cohort (n = 110) with advanced NSCLC who received osimertinib for T790M-positive acquired resistance to prior EGFR TKI therapy.

Researchers measured time to treatment discontinuation — defined as time until the end of therapy for any reason — to determine clinical outcomes of osimertinib.

Among the institutional cohort, 41 (68% women) experienced progression and underwent a resistance biopsy adequate for genomic analysis.

The median time to treatment discontinuation among patients who progressed was 8 months.

Thirteen patients maintained T790M, whereas 28 patients lost T790M.

Patients with T790M loss had a shorter time to treatment discontinuation than patients without loss (6.1 months vs. 15.2 months).

Investigators attributed shorter time to discontinuation to pre-existing resistant clones, which they observed in the validation cohort of 110 patients.

Among 28 patients who lost T790M, researchers observed various competing resistance mechanisms including small cell lung cancer transformation, MET amplifications, PIK3CA mutations and BRAF mutations.

“Treatment of drug resistance in lung cancer can be complex,” Oxnard said. “Effectively targeting one resistance mechanism, such as EGFR T790M, can reveal underlying genomic heterogeneity resulting in suppression of that mutation but emergence of a competing resistance mechanism.”

In analyses of serial plasma levels of mutant EGFR, loss of T790M at resistance appeared associated with a smaller decrease in levels of the EGFR driver mutation after 1 to 3 weeks of therapy (100% vs. 83%; P = .01). Early changes in plasma EGFR mutation levels may indicate probable resistance patterns, according to the researchers.

Whether liquid biopsies will be able capture the heterogeneous resistance detected in the study remains unknown.

“But, our limited data suggest that serial liquid biopsies on therapy are likely to be the most effective way of detecting the emergence of competing resistance mutations early on during osimertinib treatment,” Oxnard said.

The study findings could potentially apply to other lung cancer genotypes and other cancers.

“Resistance is inherently heterogeneous, and targeting a single resistance mechanism can be effective but also can result in a transient effect,” he said. “More durable disease control may require combination approaches up front to prevent resistance before it emerges.” – by Melinda Stevens

For more information:

Geoffrey R. Oxnard, MD, can be reached at Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, 450 Brookline Ave., Dana1240M, Boston, MA 02215; email: geoffrey_oxnard@dfci.harvard.edu.

Disclosures: Oxnard reports consultant fees from AstraZeneca, Ariad/Takeda, DropWorks, Inivata and Novartis; and honoraria from BioRad, Guardant and Sysmex. Please see the full study for a list of all other authors’ relevant financial disclosures.

Geoffrey Oxnard
Geoffrey R. Oxnard

Loss of the EGFR T790M mutation at time of treatment failure with osimertinib appeared associated with the development of a range of competing resistance mechanisms among patients with advanced non-small cell lung cancer, according to findings published in JAMA Oncology.

Thus, there is a need to develop strategies to detect and target multiple coexistent resistance mechanisms to achieve more durable control of drug resistance in EGFR-mutant lung cancer, according to the researchers.

“In patients with EGFR-mutant lung cancer receiving osimertinib [Tagrisso, AstraZeneca] for the EGFR T790M resistance mutation, clinicians need to keep an eye out for early resistance due to emergence of alternate resistance mechanisms,” Geoffrey R. Oxnard, MD, associate professor of medicine at Dana-Farber Cancer Institute and Harvard Medical School, told HemOnc Today. “Such patients could be candidates for combination approaches of osimertinib plus another drug, such as the addition of a MET inhibitor to target MET amplification.”

Widespread use of osimertinib — a third-generation tyrosine kinase inhibitor — has led to a clinical problem of acquired resistance. Targeted treatment approaches are in development to overcome resistance.

Oxnard and colleagues sought to understand clinical and molecular indicators for resistance in a larger cohort, in an effort to determine different molecular mechanisms of resistance and treatment approaches.

Investigators performed next-generation sequencing on tumor biopsies of patients from a multi-institutional cohort (n = 143) and validation cohort (n = 110) with advanced NSCLC who received osimertinib for T790M-positive acquired resistance to prior EGFR TKI therapy.

Researchers measured time to treatment discontinuation — defined as time until the end of therapy for any reason — to determine clinical outcomes of osimertinib.

Among the institutional cohort, 41 (68% women) experienced progression and underwent a resistance biopsy adequate for genomic analysis.

The median time to treatment discontinuation among patients who progressed was 8 months.

Thirteen patients maintained T790M, whereas 28 patients lost T790M.

Patients with T790M loss had a shorter time to treatment discontinuation than patients without loss (6.1 months vs. 15.2 months).

Investigators attributed shorter time to discontinuation to pre-existing resistant clones, which they observed in the validation cohort of 110 patients.

Among 28 patients who lost T790M, researchers observed various competing resistance mechanisms including small cell lung cancer transformation, MET amplifications, PIK3CA mutations and BRAF mutations.

“Treatment of drug resistance in lung cancer can be complex,” Oxnard said. “Effectively targeting one resistance mechanism, such as EGFR T790M, can reveal underlying genomic heterogeneity resulting in suppression of that mutation but emergence of a competing resistance mechanism.”

In analyses of serial plasma levels of mutant EGFR, loss of T790M at resistance appeared associated with a smaller decrease in levels of the EGFR driver mutation after 1 to 3 weeks of therapy (100% vs. 83%; P = .01). Early changes in plasma EGFR mutation levels may indicate probable resistance patterns, according to the researchers.

Whether liquid biopsies will be able capture the heterogeneous resistance detected in the study remains unknown.

“But, our limited data suggest that serial liquid biopsies on therapy are likely to be the most effective way of detecting the emergence of competing resistance mutations early on during osimertinib treatment,” Oxnard said.

The study findings could potentially apply to other lung cancer genotypes and other cancers.

“Resistance is inherently heterogeneous, and targeting a single resistance mechanism can be effective but also can result in a transient effect,” he said. “More durable disease control may require combination approaches up front to prevent resistance before it emerges.” – by Melinda Stevens

For more information:

Geoffrey R. Oxnard, MD, can be reached at Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, 450 Brookline Ave., Dana1240M, Boston, MA 02215; email: geoffrey_oxnard@dfci.harvard.edu.

Disclosures: Oxnard reports consultant fees from AstraZeneca, Ariad/Takeda, DropWorks, Inivata and Novartis; and honoraria from BioRad, Guardant and Sysmex. Please see the full study for a list of all other authors’ relevant financial disclosures.