Poziotinib Misses Primary Endpoint in EGFR Exon 20-Mutant NSCLC

Poziotinib did not meet its primary endpoint of overall response rate in patients with previously treated EGFR-mutant non–small cell lung cancer who have exon 20 insertion mutations.

Francois Lebel, MD, chief medical officer of Spectrum Pharmaceuticals

Francois Lebel, MD, chief medical officer of Spectrum Pharmaceuticals

Francois Lebel, MD

Poziotinib did not meet its primary endpoint of overall response rate (ORR) in patients with previously treated EGFR-mutant non—small cell lung cancer (NSCLC) who have exon 20 insertion mutations, according to topline findings from cohort 1 of the phase II ZENITH20 trial (NCT03318939).1

In cohort 1 of ZENITH20, 115 patients were enrolled and received poziotinib at 16 mg daily. Results of the intent-to-treat analysis showed that the confirmed ORR was 14.8% (n = 17; 95% CI, 8.9%-22.6%) and the disease control rate (DCR) was 68.7% (n = 79).

Additionally, the median duration of response (DOR) was 7.4 months, and the safety profile was consistent with what has been observed with poziotinib in prior studies.

“In cohort 1, poziotinib has shown unequivocal biologic activity. Although we are disappointed by the ORR, we are highly encouraged by other measures including the disease control rate, the duration of response and the predictable safety profile,” Francois Lebel, MD, chief medical officer of Spectrum Pharmaceuticals, the developer of poziotinib, stated in a press release. “A full review of cohort 1 is underway and we plan to present the data at a future medical meeting.”

Poziotinib targets relatively uncommon EGFR and HER2 exon 20 insertion mutations. In the phase II ZENITH20 trial, poziotinib as monotherapy is being evaluated across 7 cohorts based on patients’ molecular and treatment status. Cohorts 1 and 2 comprise previously treated patients with EGFR and HER2 exon 20 insertion—mutated NSCLC, respectively. Cohort 3 is assessing poziotinib in treatment-naïve patients with EGFR exon 20 insertion—mutated disease, and cohort 4 is evaluating poziotinib in treatment-naïve patients with HER2 exon 20 insertion—mutated NSCLC.

Cohort 5 is accruing previously treated and treatment-naïve patients with NSCLC who have EGFR or HER2 exon 20 insertion mutations, and cohort 6 includes patients with NSCLC with classical EGFR mutations who have disease progression on frontline osimertinib. The seventh cohort accepts patients with previously treated locally advanced or metastatic NSCLC with less common mutations in EGFR or HER2 exons 18 to 21, or the extracellular or transmembrane domains.

The primary endpoint is ORR, and secondary endpoints include DCR and DOR.

Cohorts 1 through 4 are each independently powered for a prespecified statistical hypothesis; the primary endpoint was ORR; cohorts 5 through 7 are exploratory studies. Additionally, Spectrum Pharmaceuticals stated that the futility analysis is complete for cohorts 2 and 3, which did meet their minimum threshold of responses to continue; results of these cohorts are expected to be reported in 2020.

Cohorts 4, 5, 6, and 7 are continuing per protocol, the company stated in the press release.

“While the response rate of cohort 1 in this trial was lower than we expected, the positive signals observed for this cohort provide support for the continued clinical evaluation of poziotinib in this patient population with significant unmet medical need,” Joe Turgeon, president and CEO of Spectrum Pharmaceuticals, stated in the press release. “We look forward to providing read outs from cohorts 2 and 3 in 2020, and plan to provide an update on the overall program strategy during the first quarter of 2020 after a full evaluation of the data from cohort 1 is completed.”

Previously, an open-label, single-center trial evaluated poziotinib in patients with metastatic NSCLC with EGFR or HER2 insertion or point mutations, excluding those with acquired T790M mutations. In the study, investigators administered 16 mg of oral poziotinib to 2 cohorts of patients with the exon 20 alterations, EGFR (n = 50) and HER2 (n = 13), until disease progression, death, or withdrawal. Most of the patients in both cohorts received prior therapy, respectively, with platinum therapy (86% and 77%), a TKI (34% and 15%), or a PD-1/PD-L1 inhibitor (54% and 62%). The study’s primary endpoint was ORR.

In the EGFR group, the ORR was 55% for best response and 43% for confirmed response among 44 evaluable patients. The median progression-free survival in the intention-to-treat population was 5.5 months (95% CI, 5.2—not available); 19 patients were still receiving treatment at the time of data cutoff, including 6 who were on therapy for ≥1 year.2

Twelve patients were evaluable in the HER2 cohort; the best response ORR was 50% and the confirmed ORR was 42%. The median PFS among all enrolled patients was 5.1 months and 5 patients remained on treatment.

In the safety population (n = 63), the most common all-grade treatment-related adverse events included diarrhea (69.8%), oral mucositis (69.8%), paronychia (60.3%), and dry skin (58.7%). The most frequently observed grade 3/4 AEs included skin rash (34.9%), diarrhea (17.5%), paronychia (9.5%), and nausea (7.9%). No grade 5 AEs were reported.


  1. Spectrum Pharmaceuticals provides pipeline update on late stage programs [news release]. Spectrum Pharmaceuticals. Published December 26, 2019. https://bit.ly/35itzm6. Accessed January 2, 2020.
  2. Heymach J, Negrao M, Robichaux J, et al. A phase II trial of poziotinib in EGFR and HER2 exon 20 mutant non-small cell lung cancer (NSCLC). Presented at: The IASLC 19th World Conference on Lung Cancer; September 23-26, 2018; Toronto, Canada. investor.sppirx.com/static-files/d6e05c4b-2c55-4b8c-8d7f-15b6c484f1c9. Accessed August 30, 2019.
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