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Liquid Biopsy-Guided EGFR Rechallenge Therapy Shows Benefit for Colorectal Cancer Patients

NEW YORK – New data presented this week at the American Society of Clinical Oncology's virtual annual meeting has shown that liquid biopsy testing can help optimize EGFR rechallenge by identifying patients for whom it is most likely to be successful.

The new results, from a Phase II study called CHRONOS, demonstrated objective responses in one third of patients, beating results from previous studies not guided by circulating tumor DNA.

Although molecularly targeted therapies have changed the landscape for metastatic colorectal cancer patients, options for patients dry up once a small handful of actionable biomarkers have been either exhausted or ruled out.

Hoping to maximize benefit from the treatments that are available, clinicians have been exploring new strategies in recent years for reintroducing EGFR targeting drugs in patients who previously developed resistance to them.

Presenting the results at ASCO, Andrea Sartore-Bianchi, an associate professor of oncology at the University of Milan, said that EGFR targeted therapy remains the majority player in precision oncology for colorectal cancer, but all patients eventually develop resistance to these drugs. That resistance is most often driven by the proliferation of RAS and EGFR ectodomain clones.

As circulating DNA monitoring technologies have emerged in recent years, researchers have applied them to studying these mechanisms, observing this clonal evolution emerging alongside therapy resistance, and also seeing it subside after treatment, suggesting that patients whose resistance clones have subsided might have renewed anti-EGFR drug sensitivity.

Guillem Argiles, a member of the gastrointestinal malignancies division at the Vall d’Hebrón University Hospital, served as a discussant for the study.

Investigators have trialed EGFR rechallenge previously, he said, but the first attempts had "despairing" efficacy data due to heterogeneous trial populations. Since then, clinical features have been identified, including the degree of response to prior EGFR-targeted therapy and the time interval between that and the rechallenge, which improved results to an approximately 20 percent objective response rate.

With CHRONOS, Sartore-Bianchi hoped to improve on this with a ctDNA-guided strategy.

Patients were eligible if they had achieved an objective response followed by progression on an anti-EGFR antibody regimen during any prior line of treatment and then had one or more intervening non-EGFR-targeting treatment lines. They also had to show wild-type status in their ctDNA when screened for the trial.

Enrolled patients were treated with panitumumab until progression, and researchers tracked their ctDNA by digital PCR and next-generation sequencing.

Overall, trial investigators screened 52 patients between August 2019 and November 2020, and 36 of those met the criteria of being ctDNA-negative for RAS/BRAF/EGFR mutations. Of these, 27 were enrolled across four centers.

Sartore-Bianchi said at ASCO that the study met its primary endpoint with eight partial responses, or an objective response rate of 30 percent.

In addition, 11 other patients showed stable disease with eight of those lasting more than four months.

The treatment resulted in a 63 percent disease control rate overall with median progression-free survival of 16 weeks and median duration of response of 17 weeks.

This compares favorably with the standard of care for patients undergoing second and further treatment lines, Argiles said.

Sartore-Bianchi also highlighted the group's finding that neither the presence of resistance mutations in the cohort screened for inclusion in the trial, nor the response rates in those treated were time dependent, further illustrating the benefit of ctDNA-guided treatment over empirical methods based on timing from previous treatment.

Responding patients included those treated with a prior anti-EGFR drug as little as four or five months prior, and some individuals who were deemed ineligible based on the presence of resistance mutations were years out from their most recent line of targeted therapy.

Efficacy also seemed to be independent of the number and nature of patients' prior treatments. The team even recorded responses in two right-sided colorectal cancer patients who would not have been eligible for rechallenge under the empiric clinical criteria used in prior trials.

Discussing the study, Argiles also noted the fact that 31 percent of patients failed to meet the criteria for treatment based on ctDNA screening, despite meeting the clinical criteria used to direct previous EGFR rechallenge trials.

This is clear evidence that liquid biopsy works in better tailoring the patient population, he said. However, ctDNA is also not a perfect tool, as seven patients that didn't present any mechanism of resistance in their liquid biopsy also didn't respond to treatment.

Although the trial was positive, Argiles also said that several issues may limit implementation of liquid biopsy-guided EGFR rechallenge in the clinic.

For one, the trial was not randomized, so the benefit for this strategy over standard of care hasn't been definitively proven. There is also a lack of standardization of ctDNA panels and technologies, and no single assay is established or recognized as the appropriate companion test for guiding EGFR rechallenge. As such, patient or provider access to ctDNA testing is far from universal.

During the session's question-and-answer period, Sartore-Bianchi addressed the question of whether and how clinicians without access to ctDNA testing should consider EGFR rechallenge over other chemotherapeutic and targeted options for patients who have failed multiple lines of prior treatment.

According to Sartore-Bianchi, CHRONOS included responding patients treated with some of the more promising late-stage options, so an option for clinicians could be to start with other drugs, and then consider rechallenge after that.

"I don't think rechallenge is competing against the standard of care," Argiles added. "It's about the continuum of care … [and] being able to provide to the patient as many lines as possible."