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Repeat Biomarker Testing Informs Next Steps for Treatment-Resistant EGFR-Mutant NSCLC Patients


PARIS – In a series of presentations at the European Society for Medical Oncology Congress on Sunday, researchers demonstrated how repeatedly testing advanced non-small cell lung cancer patients for biomarkers can inform treatment strategies for overcoming resistance, particularly to AstraZeneca's third-generation EGFR inhibitor Tagrisso (osimertinib).

In three studies, researchers showed that repeating molecular tests during treatment and once a patient progresses on therapy can help inform when to switch from one EGFR inhibitor to another, or to swap in treatments against acquired resistance mutations.

But in discussing the findings of these studies, oncologists also acknowledged that repeat testing may be difficult to operationalize with standard tissue-based testing, because tumor tissue gets harder to procure in advanced NSCLC patients and reliable noninvasive methods are needed. 

Switching based on ctDNA

In presenting data from the Phase II APPLE trial, Jordi Remon Masip, an oncologist with the HM Nou Delfos Hospital in Barcelona, described how, for advanced NSCLC patients who initially receive the first-generation EGFR tyrosine kinase inhibitor Iressa (AstraZeneca's gefitinib), serial blood-based monitoring for EGFR T790M mutations is a feasible way to determine when a patient should switch to the newer-generation Tagrisso, potentially before detectable disease progression.

Masip shared data from arms B and C in the ongoing study. In arm B, metastatic EGFR-mutated NSCLC patients taking Iressa underwent monthly blood plasma-based testing for EGFR T790M mutations with Roche's PCR-based Cobas EGFR Mutation Test v2. If these mutations showed up, patients were switched from Iressa to Tagrisso. Patients in this arm could also switch onto Tagrisso if their cancers progressed via more traditional imaging scans, regardless of their blood-based test results. In arm C, meanwhile, patients switched from Iressa to Tagrisso only once their cancers recurred according to imaging tests. 

In arm B, 68 percent of 47 patients switched from Iressa to Tagrisso. Twenty-five percent of those patients who switched did so based on T790M mutations that appeared in blood-based circulating tumor DNA tests before imaging-based detectable cancer progression. Of 44 patients in arm C, 77 percent switched to Tagrisso, all based on imaging-detected disease progression.

While Masip highlighted that the study wasn't meant to be a comparison between the two arms so much as an effort to show that blood test monitoring is feasible for sequencing therapy, he noted that patients who switched treatment based on ctDNA results had slightly improved outcomes in exploratory analysis versus the patients who switched to Tagrisso based on imaging alone. After 18 months, 87 percent of patients who switched to Tagrisso based on the blood tests were alive, and 67.2 percent of patients were alive without disease progression. In arm C, comparatively, 77 percent of patients were alive, and 53.5 percent were alive without disease progression.

After a median follow-up of 30 months, the median progression-free survival times in arms B and C were 22 months and 20.2 months, respectively. This, as Helena Yu, a lung cancer oncologist at Memorial Sloan Kettering pointed out in her discussion, wasn't a major improvement, even though the study was not designed to detect an improvement but show the feasibility of monthly ctDNA monitoring to inform the timing of Tagrisso switching. Toward that end, the study achieved its endpoint, she said. 

Yu commended the investigators of the APPLE study for successfully integrating monthly ctDNA testing into clinical practice, even though the strategy is not standard practice. She further noted the possibility that ctDNA could be used in this patient population as a biomarker for risk stratification and treatment escalation.

This serial monitoring, she explained, might show early on whether patients clear their EGFR ctDNA soon after starting Tagrisso or not. Then, patients in whom EGFR ctDNA is still detected after about three weeks on Tagrisso, for example, may be considered candidates for treatment escalation, potentially with chemotherapy added onto their EGFR inhibitor. Yu said that she and her colleagues at MSK are currently evaluating this strategy in an ongoing trial using Guardant Health's liquid biopsy test, Guardant360 CDx.

When to target MET resistance

Since Tagrisso is now most oncologists' go-to first-line therapy for advanced EGFR-mutant NSCLC patients, researchers also considered how to use repeat testing to flag resistance due to MET amplifications and inform a treatment strategy with Merck KGaA's Tepmetko (tepotinib). 

Julien Mazieres, an oncologist with the Toulouse Cancer Research Center in France, shared data from the Phase II INSIGHT 2 study showing that biomarker testing at the time of Tagrisso disease progression can reveal MET amplifications, against which combined treatment with Tagrisso and Tepmetko can be effective.

Mazieres presented data from advanced NSCLC patients with EGFR mutations whose cancers stopped responding to Tagrisso, 139 of whom had MET-amplified tumors at the time of progression, as determined by fluorescence in situ hybridization, and 47 of whom were positive for MET gene amplifications using ArcherDx's blood-based sequencing test, ArcherMET.

While the study is still ongoing, Mazieres presented overall response data from one group, highlighting a 54.5 percent confirmed response rate to Tagrisso plus Tepmetko after nine months of follow-up among 22 patients with MET-amplified tumors according to FISH when they progressed on Tagrisso. Among 12 patients whose tumors were MET amplified according to FISH but received just Tepmetko after progression, as opposed to both drugs, only one patient had a partial response.

The study showed that combined Tagrisso and Tepmetko treatment is an effective way to treat patients after Tagrisso progression determined via repeat biomarker testing at the time of relapse. The results also showed, however, that Tepmetko alone after Tagrisso is not very effective treatment.

"MET amplification can be effectively targeted using MET plus EGFR [inhibitor] combination therapy," Yu said in her discussion of the INSIGHT 2 data, adding that "further work is needed to define appropriate MET biomarkers" because even though the research supports the value of testing for MET-based Tagrisso resistance biomarkers generally, the available testing methods — including FISH, next-generation sequencing (NGS), and immunohistochemistry — have different capabilities when it comes to gauging MET abnormalities.

Challenge with tissue-based NGS

Finally, Zofia Piotrowska, a lung cancer oncologist at the Massachusetts General Hospital, shared data from the Phase II ELIOS study showing that molecular profiling is an important tool for determining Tagrisso resistance mechanisms and selecting the best next treatment. She also showed that it is difficult, and sometimes impossible, to obtain sufficient tissue samples for NGS profiling of patients who progress on Tagrisso.

The ELIOS trial, which is the first prospective study to compare paired baseline tissue biopsies with tissue biopsies obtained after Tagrisso progression, used Foundation Medicine's FoundationOne CDx to identify acquired mutations that confer resistance to Tagrisso. In 119 NSCLC patients whose cancers progressed on Tagrisso, however, only 46, or 39 percent, actually wound up eligible for the paired analysis, which Piotrowska chalked up to the "technical failures of the NGS." Indeed, it is often difficult to obtain a sufficient tissue sample for NGS testing in this advanced NSCLC patient population, which presents a challenge for demonstrating the utility of comprehensive tumor profiling tests.

The researchers still gleaned valuable insight from the 46 evaluable patients, identifying, for instance, that eight patients had acquired MET amplification and five patients had acquired the EGFR C797S resistance mutation, both of which could potentially be treated with existing or new targeted drugs. The researchers also found a potential new resistance mutation, NKX2.1, among five of these patients.

That said, perhaps the biggest takeaway was the reminder that in an advanced NSCLC patient population, especially in those previously treated, procuring tissue biopsies for molecular analysis is extremely difficult. More than half of the patients in the ELIOS study were ultimately not evaluable for this very reason. "This tells me it is very hard to obtain [these] biopsies," Yu said.

Regardless, both Piotrowska and Yu highlighted the clear benefit of repeat biomarker testing for Tagrisso resistance mutations, many of which are clinically actionable. "In my opinion, all patients should get some sort of molecular testing after progression on first-line [Tagrisso]," Yu said.