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Valentina Boni



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    OA04 - New Data from Rare EGFR Alterations (ID 223)

    • Event: WCLC 2020
    • Type: Oral
    • Track: Targeted Therapy - Clinically Focused
    • Presentations: 1
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      OA04.06 - Neratinib in Pretreated EGFR Exon 18-Mutant Non-Small Cell Lung Cancer (NSCLC): Initial Findings From the SUMMIT Basket Trial (ID 4219)

      11:45 - 12:45  |  Presenting Author(s): Valentina Boni

      • Abstract
      • Presentation
      • Slides

      Introduction

      EGFR exon 18 mutations are rare, representing approximately 3–5% of EGFR mutations in NSCLC [cBioPortal 2020; Sharma et al. 2007]. Preclinical data indicate that EGFR exon 18 (G719X) mutations are highly sensitive to neratinib [Kobayashi et al. 2015], an irreversible pan-HER tyrosine kinase inhibitor (TKI), compared with other approved first- and second-generation EGFR TKIs. A phase 2 trial of neratinib in 167 patients with EGFR-mutated NSCLC showed 3 PRs and 1 SD with a mPFS of 52.7 weeks in 4 patients with exon 18 mutations (G719X) [Sequist et al. 2010]. We present data from the EGFR exon 18-mutant NSCLC cohort treated with neratinib monotherapy in the phase 2 SUMMIT basket trial (NCT01953926).

      Methods

      Patients with histologically confirmed NSCLC with documented EGFR exon 18 mutation, who were naïve to or previously treated with EGFR TKIs, with an ECOG status of 0–2, were treated with neratinib (240 mg po daily). Prior chemotherapy and/or checkpoint inhibitors (IO) were allowed. Patients received mandatory diarrhea prophylaxis with loperamide (first 6 weeks, then PRN). Study endpoints were: objective response rate (ORR) at week 8 (+/– 1 week); ORR (RECIST 1.1 confirmed); duration of response (DOR); clinical benefit rate (CBR); PFS; safety (NCI CTCAE, v4.0); biomarkers.

      Results

      11 patients with EGFR exon 18-mutant NSCLC were enrolled and evaluable for efficacy/safety. Baseline characteristics: median age 67 (range 56–83) years; male (55%), white (91%); ECOG PS 0/1 (45%/55%). Median prior lines of metastatic therapies: 2 (range 1–3). Prior treatments: first- and second-generation EGFR TKIs (91%); chemotherapy (55%); IO (27%). 3/11 patients had a single G719X mutation. 1 patient had an exon 18 inframe mutation (E709delinsD). The remaining 7 patients had G719X plus ≥1 additional co-EGFR mutation (E709X, S768I, T790M). The safety profile of neratinib showed that diarrhea was the most common adverse event, but diarrhea severity was lower than reported previously [grade 1, 4 patients (36%); grade 2, 1 patient (9%); no grade ≥3 diarrhea]. No pneumonitis adverse events were reported. Efficacy results of TKI-pretreated patients are summarized in the table.

      Parameter TKI-pretreated
      patients (n=10)a

      ORR (confirmed),b,† n
      CR
      PR
      ORR, % (95% CI)

      4
      0
      4
      40 (12–74)

      Best overall response, n
      CR
      PR
      Best overall response rate, % (95% CI)

      6
      0
      6
      60 (26–88)
      Median DOR,c months (95% CI)

      7.5 (4.0–NE)

      (1.9*, 4.0, 7.5, 9.2*)

      CBR,d n
      CR or PR
      SD ≥16 weeks
      CBR, % (95% CI)

      8
      4
      4
      80 (44–97)
      Median PFS,c months (95% CI) 9.1 (3.7–NA)

      a10 out of 11 patients were previously treated with EGFR TKIs.

      bORR (objective response rate) defined as either a CR or PR that is confirmed no less than 4 weeks after the criteria for response are initially met.

      cKaplan-Meier analysis in safety population.

      dCBR (clinical benefit rate) defined as confirmed CR or PR or SD for ≥16 weeks (within +/– 7-day visit window).

      †Data for ORR at week 8 (ORRfirst) and ORR (RECIST 1.1 confirmed) are identical and are only presented once.

      *Response ongoing.
      Conclusion

      Neratinib 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. The ORR and mPFS appeared better than reported in the literature for other EGFR TKIs in TKI-refractory patients. Further evaluation of neratinib in patients with NSCLC and this uncommon EGFR mutation is ongoing.

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