Emerging options for NSCLC with rare EGFR mutations
medwireNews: Promising early data on several novel treatment options for non-small-cell lung cancer (NSCLC) harboring rare EGFR alterations have been reported at the IASLC 2020 World Conference on Lung Cancer.
Mobocertinib active against NSCLC harboring EGFR exon 20 insertions
Caicun Zhou (Shanghai Pulmonary Hospital, China) presented data on mobocertinib (formerly TAK-788), a first-in-class tyrosine kinase inhibitor (TKI) that targets EGFR exon 20 insertions, in patients with locally advanced or metastatic NSCLC harboring such mutations.
As previously reported by medwireNews, the agent achieved an objective response rate (ORR) of 43% among the initial 28 participants of the multicohort phase 1/2 trial.
The current report focused on 96 previously treated patients enrolled in the EXCLAIM extension cohort and on 114 participants from across the trial (including the EXCLAIM cohort) who had received prior platinum-based therapy. The data cutoff for this analysis was May 29, 2020.
Treatment with oral mobocertinib at a daily dose of 160 mg led to an independently assessed ORR of 23% in the EXCLAIM cohort and 26% in the platinum-treated cohort. A further 52% and 53% of patients had stable disease for at least 6 weeks, giving a disease control rate of 78% and 76%, respectively.
The median progression-free survival (PFS) time by independent review was 7.3 months in the EXCLAIM and platinum-treated groups, and the corresponding median durations of response were unreached and 17.5 months.
Grade 3 or more severe treatment-related adverse events (TRAEs) were observed in 46% of patients in the EXCLAIM cohort and 41% of those in the platinum-treated cohort (most commonly diarrhea in both), with a respective 17% and 10% discontinuing the study drug due to toxicity. One TRAE in a platinum-treated participant of the EXCLAIM cohort was fatal.
Mobocertinib showed a “clinically meaningful benefit” and “a manageable safety profile,” in this patient population, summarized Zhou.
Amivantamab another option for EGFR exon 20 insertions
Reporting on the phase 1 CHRYSALIS trial of amivantamab (formerly JNJ-372), Joshua Sabari (New York University, USA) explained that the bispecific antibody targeting EGFR and MET has shown preliminary efficacy against EGFR exon 20 insertion mutations in the dose-escalation part of the study.
He presented the outcomes of 81 participants of the exon 20 insertion dose-expansion cohort, all of whom had progressed on platinum-based chemotherapy and had at least three disease assessments following treatment with intravenous amivantamab at a dose of either 1050 or 1400 mg depending on bodyweight (<80 or ≥80 kg, respectively), given weekly in the first 28-day cycle and every 2 weeks subsequently.
Over a median follow-up of 9.7 months, 40% of patients had a response – as assessed by blinded review – lasting for a median of 11.1 months, and 74% derived a clinical benefit, defined as a complete or partial response or stable disease at two or more assessments.
The median PFS and overall survival (OS) times were 8.3 and 22.8 months, respectively.
In the safety population, which comprised 114 platinum-treated patients with exon 20 insertions, 16% had a TRAE of at least grade 3, most commonly rash (4%) and infusion-related reactions (3%). The rate of discontinuation due to AEs was 4% and there were no deaths due to TRAEs.
“Based on amivantamab’s efficacy, combination approaches are currently being pursued,” including alongside chemotherapy in the phase 3 PAPILLON study and together with lazertinib in the phase 3 MARIPOSA trial, concluded Sabari.
Neratinib shows promise for EGFR exon 18-mutated NSCLC
Valentina Boni (START Madrid-CIOCC, Spain) outlined the initial results of 10 patients with EGFR exon 18 mutations included in the phase 2 SUMMIT basket trial of the pan-HER–TKI neratinib, which has been shown to be active against these mutations in preclinical studies and an earlier phase 2 study.
All patients included in the current report had previously been treated with EGFR– or pan-HER–TKIs (such as gefitinib, osimertinib, and afatinib), and three had a single G719X mutation, while the remaining seven patients additionally harbored at least one other EGFR mutation, such as S768I and T790M.
In all, 40% of participants achieved an objective response after receiving oral neratinib 240 mg/day, and an additional 40% had stable disease for at least 16 weeks, which gave a clinical benefit rate of 80%. The median duration of response was 7.5 months and the median PFS was 9.1 months.
Neratinib was “[w]ell-tolerated with no evidence of grade 3 diarrhea with mandatory loperamide prophylaxis,” which was required during the first two cycles, said Boni.
Among the safety-evaluable participants, which additionally included one patient who had not received prior TKI, four patients had grade 1 and one had grade 2 diarrhea; there were no dose interruptions, reductions, or discontinuations as a result of this AE. There was just one AE of grade 3 or worse, namely decreased appetite.
Boni therefore concluded that “[n]eratinib monotherapy showed meaningful activity in EGFR TKI-pretreated patients with EGFR exon 18-mutant NSCLC, a group for whom very few effective options exist once they fail EGFR TKIs.”
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