Almonertinib Induces Response in EGFR T790M-Positive NSCLC With CNS Metastases
May 05, 2020 05:00pm
By Danielle Ternyila
Interim findings of the ongoing phase II ZENITH20 trial demonstrated that poziotinib induced a 68.7% disease control rate when used as treatment of patients with pretreated non–small cell lung cancer harboring an EGFR exon 20 insertion.
A disease control rate (DCR) of 68.7% was observed with poziotinib systemic therapy as treatment of patients with pretreated non–small cell lung cancer (NSCLC) harboring an EGFR exon 20 insertion, according to interim findings from the ongoing, pivotal phase II ZENITH20 clinical trial (NCT03318939), which were presented at the 2020 American Association for Cancer Research Annual Meeting.1
According to Xiuning Le, MD, PhD, who presented the findings to a virtual audience, responses occurred relatively early and patients who had dose interruptions or delays were observed to have maintained responses with poziotinib.
"Looking at subgroups of patients, response rates were maintained across lines of therapy even in heavily pretreated patients who had 3 or more lines of therapy," Le, assistant professor in the Department of the Thoracic/Head and Neck Medical Oncology in the Division of Internal Medicine at The University of Texas MD Anderson Cancer Center in Houston, Texas, said to the audience. "This included patients who had [been treated with] previous EGFR TKIs [tyrosine kinase inhibitors]."
The objective response rate (ORR) in this patient cohort was 14.8% (95% CI, 8.9%-22.6%). Seventy-nine of the 115 patients in the intention-to-treat population had stable disease or better, and the median duration of response was 7.4 months (95% CI, 3.7-9.7).
The median progression-free survival (PFS) in this patient subset was 4.2 months (95% CI, 3.7-6.6).1 This compared favorably with a historical cohort of patients with EGFR exon 20 insertion mutations treated with first- or second-generation TKIs who demonstrated a median PFS of 2 months versus 14 months observed in patients with classical EGFR mutations (exon 19 deletions and the mutations encoding p.L858R and p.L861Q).2
Although the primary end point of ORR was not meet with only 17 out of 115 patients having a complete or partial response, Le said tumor shrinkage was achieved in 75 (65%). Previously, a single-center trial of poziotinib conducted at MD Anderson Cancer Center showed a higher rate of confirmed responses at 43% in patients with heavily pretreated EGFR or HER exon 20–mutant disease who received poziotinib therapy.3
A significant portion of patients treated with the full dose of poziotinib at 16 mg had dose interruptions or reductions, but responses were maintained at a lower dose level. Dose reductions occurred in 68% of patients. Using the median relative dose intensity of 72% (range, 7%-100%) and a 16-mg dose as the denominator, the average dose was about 11.5 mg, said Le.
Drug interruptions were required for 97 patients (88%), with a median duration of first dose interruption of 16 days. Permanent discontinuation due to treatment-related adverse events (TRAEs) happened at a rate of 10%.
Compared against other second-generation EGFR TKIs, dose reduction and discontinuation rates were similar with poziotinib. Data from the LUX-Lung 3 (NCT00949650) and ARCHER 1050 (NCT01774721) trials of patients with EGFR-mutant NSCLC demonstrated similar rates of dose reduction and discontinuation for afatinib (Gilotrif), at 52% and 8%, and dacomitinib (Vizimpro), at 66% and 10%, respectively.4,5
ORR was fairly consistent across patient subgroups at 14.3%, 13.8%, and 16.2% in patients with one, 2, or 3 or more lines of therapy, respectively. The greatest ORRs were observed in those without prior EGFR TKI therapy (17.4%), no brain metastases (15.5%), and an ECOG performance status of 0 (18.9%).
"These data are consistent with the function of TKIs with on-target activity," Le said.
Any-grade TRAEs were observed in 114 patients (99%), with the most common being diarrhea (79%), rash (60%), stomatitis (52%), and paronychia (45%). Grade 3 TRAEs occurring in more than 10% of patients were diarrhea (25%) and rash (28%). There were 2 grade 4 events, one each of diarrhea and dermatitis acneiform, and no grade 5 TRAEs.
Patients analyzed in this presentation were those treated in cohort 1 of the trial, which included patients with previously treated EGFR-positive NSCLC. Patients receiving treatment in cohorts 2 through 4 of the trial include those with and without prior therapy and all patients’ tumors had either EGFR or HER2exon 20 insertions.
Le noted that baseline characteristics in this cohort revealed a young (median age, 61 years), and majority female (67%) population, with a high rate of patients who identified as never smokers (69%). Most patients had adenocarcinoma histology (98%), stage IV disease (91%), and no brain metastases (90%). Patients who had received 3 or more prior lines of therapy accounted for 32% of participants and 75% had no treatment experience with EGFR TKIs.
Of the multiple EGFR small-molecule TKIs approved for use in in this patient population, none are currently FDA approved to treat tumors with EGFR exon 20 insertions that account for about 10% of all EGFR mutations.1 Patients harboring mutations in EGFRexon 20 have not demonstrated sensitivity to available therapy, and Le said this may be due to a difference in molecular structure compared with classical EGFR mutations. Exon 20 insertions create a shallow and relatively small interaction surface at the ATP binding pocket of the EGFR protein, which renders these mutations resistant to available therapies.2 The small size and shape of poziotinib allows for binding in the pocket of exon 20.1
The trial is ongoing with 3 added cohorts: cohort 5 will include patients with EGFR or HER2 exon 20 insertions who missed the enrollment window for treatment in cohorts 1 through 4 (n = 180); cohort 6 will examine patients with acquired EGFR mutations following first-line osimertinib failure (n = 30); and patients with EGFR or HER2 activating mutations will be treated in cohort 7 (n = 30). The new cohorts will examine twice-daily dosing of poziotinib to determine if the split-dose strategy reduces the incidence of adverse events and improves patient compliance.