Correlation Between ctDNA Clearance and PFS Improvement Demonstrated in EGFR+/MET+ NSCLC

For patients with EGFR-mutant, MET-amplified non–small cell lung cancer (NSCLC) with detectable ctDNA at baseline, circulating tumor DNA (ctDNA) clearance of EGFR mutation may be predictive of extended progression-free survival (PFS), according to data from the TATTON study (NCT02143466) presented during the 2020 American Association for Cancer Research (AACR) Virtual Annual Meeting II.

The phase 1 study evaluated the combination of osimertinib (Tagrisso), a third-generation EGFR tyrosine kinase inhibitor (TKI), and savolitinib, an investigational highly selective MET TKI. Part B and D of the TATTON study were assessed to determine if ctDNA clearance of EGFR sensitizing mutations with exon 19 deletions and L858R in those receiving savolitinib plus osimertinib was indicative of PFS.

MET amplifications are found in up to 10% of patients with EGFR-mutant NSCLC who progress on first- or second-generation EGFR TKIs and in up to 25% of those who progress on a third-generation EGFR TKIs, necessitating the need for treatment options in the population.

ctDNA Clearance in Patients With Baseline Detectable EGFR

Part B of the TATTON study was portioned into 3 dose-expansion cohorts, which consisted of patients with prior third-generation EGFR TKI (part B1), patients with EGFR T790M–negative tumors who had no prior third-generation EGFR TKI (part B2), and those with T790M-positive tumors who had no prior third-generation therapy (part B3). Overall, there were 69 patients in the part B1 cohort, 51 patients in part B2, and 18 patients in part B3.

A post-hoc ctDNA analysis was conducted to determine whether longitudinal clearance of baseline detectable ctDNA could, in fact, be a predictor of PFS in patients with EGFR-mutant MET-amplified NSCLC.

“The aim of this analysis was to assess whether longitudinal ctDNA clearance at baseline, could be a predictor of progression-free survival. ctDNA clearance was defined for patients with a detectable EGFR mutation at baseline that then became undetectable or dropped below 0.5% allele frequency in a longitudinal sample, assessed by the Resolution BioScience ctDX lung assay,” Hartmaier stated.

Hartmaier et al conducted ctDNA sampling every 6 to 8 weeks, which was dependent on the date of the protocol amendment. The majority of the longitudinal samples were collected at cycle 3, day 1; cycle 4, day 1; or cycle 5, day 1. Research suggested that the bulk of ctDNA clearance occurred at the cycle 3, day 1 or the cycle 4, day 1 timepoints.

The analysis included 49 patients from part B, all of whom had at least 1 longitudinal sample at or before cycle 6, day 1, and 42 from part D, who all had samples from day 1 of cycles 1 and 4. Of the patients evaluable for the ctDNA analysis from Part B, 11 had an undetectable EGFR mutation at baseline versus 38 who were detectable. Among the patients from Part D, 4 had an undetectable EGFR mutilation at baseline and 18 had a detectable EGFR.

Using a waterfall plot, Hartmaier presented the difference in EGFR-mutant allele frequency from baseline at cycle 2, day1/cycle 4, day 1 in patients with baseline detectable ctDNA from part B (n = 34). As of the data cutoff date of February 18, 2018, the best response was partial response (PR).

Hartmaier noted, “this clearly shows that most patients display a major molecular response to this combination therapy. Patients who experienced a partial response tended to see significant drops in ctDNA levels as well.”

Regarding PFS probability by ctDNA clearance at cycle 3, day 1/cycle 4, day 1 in part B patients with detectable baseline ctDNA, the median PFS was 3.9 months (95% CI, 2.7-6.0 months) in patients without ctDNA clearance. For patients with ctDNA clearance, the median PFS was 9.1 months (95% CI, 5.4-not calculable). The hazard rate for the difference between these patient groups was 0.34 (95% CI, 0.14-0.81; P =.0146).

The post-hoc analysis also explored whether ctDNA was altered across analogous cohorts dosed with either savolitinib 600 mg or 300 mg. The patients in this portion of the analysis were from part B2 and D, had no prior EGFR TKI therapy, and had T790M-negative disease.

Out of 13 patients from part B2 and 16 from part D, ctDNA clearance was observed in 50% and 65% of patients, respectively. The percentage change in EGFR-mutant allele frequency from baseline was relatively similar and there were partial responses and stable disease observed in both groups.

General Efficacy of Osimertinib Plus Savolitinib

As of the data cutoff date of March 2019, the objective response rate (ORR) for the B1 cohort was 30% (95% CI, 20%-43%). The median PFS in this cohort was 5.4 months (95% CI, 41.-8.0) and the median duration of response (DOR) was 7.9 months (95% CI, 4.0-10.5 months).

In the B2 cohort, the ORR was higher than cohort B1, at 65% (95% CI, 50%-78%). The median PFS observed in this group was 9.0 months (95% CI, 5.5-11.9). The median DOR was also 9.0 months (95% CI, 6.1-22.7).

Finally, part B3 had the greatest efficacy, with an ORR of 67% (95% CI, 41%-87%) and a median PFS of 11.0 months (95% CI, 4.0-not reached [NR]). The median DOR was 12.4 months (95% CI, 2.8-NR).

In part D, treatment with savolitinib plus osimertinib in 42 patients led to an ORR of 64% (95% CI, 46%-79%). The median PFS was 9.1 months (95% CI, 5.4-12.9) with a median DOR of 8.0 months (95% CI, 4.5 -NR), which was comparable to the data observed in part B2, Ryan Hartmaier, PhD, associate director of Translational Medicine, Oncology R&D, AstraZeneca, said during a presentation of the data.

To further assess the activity of this combination, savolitinib 300 mg is being used in ongoing studies in combination with osimertinib 80 mg. The single-arm phase 2 SAVANNAH study (NCT03778229) is evaluating the combination in patients with EGFR-mutant/MET-positive NSCLC following prior osimertinib and the phase 2 platform study ORCHARD (NCT03944772) is evaluating the combination in patients with advanced NSCLC who progressed on frontline osimertinib.

_Reference:

_{Hartmaier R, Jan JY, Ahn MJ, et al. The effect of savolitinib plus osimertinib on ctDNA clearance in patients with EGFR mutation positive (EGFRm) MET-amplified NSCLC in the TATTON study. Presented at: 2020 American Association for Cancer Research Virtual Annual Meeting II; June 22-24, 2020. Abstract CT303. https://bit.ly/2B2C4sq}