TKI Combination Shows Promise Against MET Resistance in EGFR+, MET-Amplified NSCLC

Savolitinib (AZD6094) demonstrated the ability to overcome MET resistance in patients with EGFR-mutant, MET-amplified or -overexpressed non–small cell lung cancer (NSCLC) when combined with osimertinib (Tagrisso), and these benefits extended to those with disease that had previously progressed on a prior EGFR tyrosine kinase inhibitor (TKI). These results from the final analysis of the expansion cohorts of the phase 1b TATTON study (NCT02143466) were presented virtually at the 2020 World Conference on Lung Cancer Singapore.¹

In part B of the trial, which had 3 cohorts, results showed that the overall response rate (ORR) was 33% (95% CI, 22%-46%) in cohort 1, in which patients had received a prior third-generation EGFR TKI. Cohort 2, in which patients did not have a prior third-generation EGFR TKI and were T790M-negative, showed an ORR of 65% (95% CI, 50%-78%).

In cohort 3, where patients had no prior third-generation EGFR TKI and were T790M-positive, the ORR was 67% (95% CI, 41%-87%). Overall, in part B, the ORR was 68%.

Lastly, in patients who were included in part D of the study, with no prior third-generation EGFR TKIs and were T790M-negative, the ORR was 62% (95% CI, 46%-76%).

Patients enrolled on the part B portion experienced a median progression-free survival (PFS) of 5.5 months (95% CI, 4.1-7.7), 9.1 months (95%, 5.5-12.8), and 11.1 months (95% CI, 4.1-22.1) in cohorts 1 through 3, respectively, with an overall median PFS of 7.6 months (95% CI, 5.5-9.2). In part D of the study, the median PFS was 9.0 months (95% CI, 5.6-12.7).

The regimen was also found to be safe among the population.

“Osimertinib plus savolitinib was generally well tolerated,” lead study author Ji-Youn Han, MD, a medical oncologist at the National Cancer Center Korea, said during a virtual presentation on the data. “The 300 mg dose in part D [elicited] a slightly improved safety profile with similar antitumor activity [compared with the 600-mg dose].”

While EGFR TKIs are generally recommended for the first-line treatment of patients with locally advanced or metastatic EGFR-mutated NSCLC, resistance likely occurs.^2-5 Preliminary data have indicated that osimertinib, a third-generation oral EGFR TKI, and savolitinib, an oral MET TKI, may be able to overcome MET-amplifiedor -overexpressed resistance to EGFR TKIs.

In the expansion cohorts of the 4-part, open-label, multicenter, phase 1b TATTON trial, investigators examined the safety and efficacy of osimertinib combined with savolitinib in this patient population.

To be eligible for enrollment, patients needed to be 18 years or older, with the exception of patients from Japan, who needed to be aged 20 years or older. Moreover, patients needed to have been diagnosed with locally advanced or metastatic EGFR-mutated NSCLC. Additionally, MET overexpression or amplifications needed to be confirmed by fluorescence in situ hybridization, immunohistochemistry, or next-generation sequencing and retrospective central confirmation. A World Health Organization performance status of 0 or 1 was required.

Those who enrolled in the part B cohorts were administered osimertinib at 80 mg daily along with 600 mg (n = 130) or 300 mg (n = 8) of savolitinib daily, according to weight-based dosing. Patients enrolled in the part D cohort (n = 42) were given the same dosing of osimertinib as the part B cohorts, but 300 mg daily of savolitinib.

The primary objective of the study was to evaluate the safety and tolerability of the combination, with key secondary end points consisting of ORR, PFS, and pharmacokinetics. The data cut-off date was March 4, 2020.

The majority of patients enrolled in both parts B and D of the study were female (59% and 60%, respectively) at a median age of 59 years in the part B cohorts and 63 in the part D cohort. In the part B cohorts, 72% of patients were Asian and 28% were white, whereas in the part D cohort, 67% were Asian and 33% were white. Sixty-three percent of patients in the part B cohort had an ECOG performance status of 1 and 37% had a status of 0; these rates were 64% and 36% of patients in the part D cohort, respectively.

In the part B cohorts, patients received 1 (32%), 2 (30%), 3 (16%), or more than 3 (22%) prior lines of therapy. Whereas in the part D cohort, 67% had received 1 prior line of therapy, 14% received 2, 12% received 3, and 7% more than 3 lines of therapy.

Additional data indicated that 49% of patients in the part B cohorts experienced partial responses (PRs) to the combination. Thirty-four percent of patients achieved stable disease (SD), 8% experienced progressive disease (PD), and 9% were not evaluable. In these cohorts, the combination elicited a disease control rate (DCR) of 83%, as well as a median duration of response (DOR) of 9.8 months (95% CI, 6.9-12.9).

Moreover, in the part D cohort, 62% of patients experienced a PR, 31% achieved SD, 2% experienced PD, and 5% were not evaluable. Patients in this cohort had a DCR of 93% and a median DOR of 9.7 months (95% CI, 4.5-14.3).

Additionally, Han explained, "The pharmacokinetics data for savolitinib and osimertinib were quite consistent with other patient populations in TATTON and previous clinical trials.”

Regarding safety, nearly all patients across cohorts part B and D experienced any-grade adverse effects (AE; 100% and 98%, respectively). AEs leading to death occurred in 5% each of patients in the part B and part D cohorts. The most common serious any-grade AEs in the part B cohorts included pneumonia (5%), anaphylactic reaction (4%), pneumothorax (4%), pyrexia (4%), and dyspnea (4%). In part D, common serious any-grade AEs included pneumonia (10%), pulmonary embolism (5%), anaphylactic reaction (2%), pneumothorax (2%), drug hypersensitivity (2%), and diarrhea (2%).

The most common grade 3 or higher AEs causally related to savolitinib in the part B cohort included decreased neutrophil count (7%), aspartate aminotransferase (AST) increases (6%), and alanine aminotransferase (ALT) increases (5%). In part D, this included drug hypersensitivity (7%), diarrhea (5%), generalized edema (5%), and myalgia (5%).

Osimertinib-related AEs that were grade 3 or higher included decreased neutrophil count (6%), ALT increases (4%), and AST increases (4%) in the part B cohort, and diarrhea (5%) drug hypersensitivity (5%), and myalgia (5%) in the part D cohort.

The efficacy of osimertinib plus savolitinib will be further explored in this patient population through the global phase 2 SAVANNAH trial (NCT03778229), as well as the phase 2 biomarker-directed ORCHARD study (NCT03944772).

References:

1. Han JY, Sequist LV, Ahn MJ, et al. Osimertinib + savolitinib in patients with EGFRm MET-amplified/overexpressed NSCLC: Phase Ib TATTON Parts B and D final analysis. Poster presented at: 2021 World Conference on Lung Cancer Singapore; January 28-21, 2021; Virtual. https://bit.ly/3cl7QRE

2. Metastatic non-small-cell lung cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. ESMO. Updated September 15, 2020. Accessed January 28, 2020. https://bit.ly/3j1Z2Bt

3. Oxnard GR, Hu Y, Mileham KF, et al. Assessment of resistance mechanisms and clinical implications in patients With EGFR T790M-positive lung cancer and acquired resistance to osimertinib. JAMA Oncol. 2018;4(11):1527-1534. doi:10.1001/jamaoncol.2018.2969

4. Papadimitrakopoulou VA, Wu YL, Han JY, Analysis of resistance mechanisms to osimertinib in patients with EGFR T790M advanced NSCLC from the AURA3 study. Ann Oncol. 2018;29:viii741. doi:10.1093/annonc/mdy424.064

5. Piotrowska Z, Isozaki H, Lennerz JK, et al. Landscape of acquired resistance to osimertinib in EGFR-mutant NSCLC and clinical validation of combined EGFR and RET inhibition with osimertinib and BLU-667 for acquired RET fusion. Cancer Discov. 2018;8(12):1529-1539. doi:10.1158/2159-8290.CD-18-1022