乌鸦传媒

ATLANTA -- Combining the investigational with the anti-EGFR agent osimertinib (Tagrisso) yielded partial responses in lung cancer patients who developed MET-driven resistance to EGFR-directed therapies, results from two dose-expansion arms of the TATTON trial found.

In one cohort from the phase Ib study, 52% of non-small cell lung cancer (NSCLC) patients with MET-based resistance to first- or second-generation EGFR inhibitors had an objective response following treatment with the MET/EGFR-targeted strategy, with an additional 35% achieving stable disease, reported Lecia Sequist, MD, of Massachusetts General Hospital in Boston.

And in a second cohort of the trial, 25% of patients treated with third-generation EGFR inhibitors (including osimertinib) had objective responses with the two agents while 44% achieved stable disease.

"Our data suggest that the combination of osimertinib and savolitinib could overcome MET-driven resistance, but certainly further research is needed," Sequist said during a press briefing here at the American Association for Cancer Research (AACR) meeting.

No complete responses were observed in either cohort. Median durations of response for patients exposed to the third- and earlier-generation anti-EGFR drugs were roughly 9 and 7 months, respectively, Sequist said.

"It's really personalized medicine on steroids," AACR discussant Roy Herbst, MD, PhD, of Yale Cancer Center in New Haven, Connecticut, told 乌鸦传媒, explaining that while all patients with EGFR-mutant NSCLC develop resistance to EGFR inhibitors, researchers are now figuring out what to do next when this occurs.

Resistance as a result of MET amplification occurs in 5% to 10% of patients treated on earlier-generation EGFR tyrosine kinase inhibitors (TKIs). But with third-generation agents such as osimertinib, which last year gained in EGFR-mutant NSCLC, roughly 25% of patients develop MET-based resistance.

"That's nice because when patients become resistant, we now have this new target that we can use," said Herbst. "And the savolitinib data actually looked quite compelling."

In the cohort exposed to third-generation TKIs (n=48), a majority of patients (54%) had already received three or more prior lines of therapy, including chemotherapy and other EGFR-targeted agents. In the cohort exposed to the first- and second-generation TKIs (n=46), two-thirds of patients had just one prior line of therapy while 20% had three or more.

Sequist told 乌鸦传媒 that the lower response rates in the more heavily treated group may in part reflect a sicker patient population. "But also their tumors might have been more heterogeneous," she said. "The MET amplification may not have been as focused, and we're certainly going to do some further studies to look at that."

Herbst noted that as is often the case in lung cancer, the savolitinib results would likely be even better if the drug was used earlier, perhaps as a first-line resistance therapy for those with MET amplification. "Patients are fitter, have fewer comorbidities and side effects, and can tolerate the drugs even better," he said.

Patients in these two were treated with the third-generation EGFR inhibitor osimertinib at 80 mg each day and savolitinib at 600 mg daily, with both administered orally. Participants were only enrolled if they had proven MET-driven resistance on a tissue biopsy at the primary treatment site -- either by fluorescence in situ hybridization (FISH), next-generation sequencing, or immunohistochemistry. Confirmation by FISH was then performed by central review, though not all patients had confirmed MET amplification, with the most common reason being insufficient tissue for testing. A number of patients with unconfirmed MET-based resistance in both cohorts still achieved partial responses with the combination.

Sequist said two phase II studies -- the ongoing and the planned ORCHARD trial -- will aim to clarify whether savolitinib plus osimertinib works better in certain biomarker-defined populations.

"With better selection and more knowledge I think this could become a very useful tool in the refractory EGFR setting," said Herbst.

Most patients in the two cohorts were Asian (≥77%) and had adenocarcinoma (≥89%), and the median age was 59 in both. Roughly half the patients in each group had brain metastases at baseline. In patients with prior third-generation EGFR TKI treatment, the majority were men (56%) and more than two-thirds had previously been exposed to osimertinib. In the cohort exposed to the earlier-generation EGFR TKIs, two-thirds were women.

Adverse events were similar between the two groups, consisting primarily of grade 1/2 gastrointestinal toxicities. In the third-generation cohort, common grade ≥3 AEs included decreased appetite (6%), fatigue (4%), and vomiting (4%).

In the earlier-generation cohort, the most common grade ≥3 events included increased liver enzymes (8%), decreased neutrophil counts (8%), pain (7%), decreased appetite (7%), as well as nausea, vomiting, and rash (4% each).