Poziotinib Elicits Encouraging Responses in EGFR Exon 20–Mutated NSCLC

Article

Poziotinib produced an encouraging overall response rate in patients with non–small cell lung cancer harboring EGFR exon 20 mutations, meeting the primary end point in cohort 1 of a phase 2 trial.

Yasir Y. Elamin, MD

Yasir Y. Elamin, MD

Poziotinib produced an encouraging overall response rate (ORR) in patients with non–small cell lung cancer (NSCLC) harboring EGFR exon 20 mutations, meeting the primary end point in cohort 1 of a phase 2 trial (NCT03066206), according to findings published in Cancer Cell.1 Notably, poziotinib sensitivity was highly dependent on the location of exon 20 insertions, with data showing that near-loop insertions were more sensitive to the EGFR TKI than far-loop insertions.

Data showed that patients treated with poziotinib (n = 50) achieved an investigator-assessed ORR of 32% (95% CI, 20.7%-45.8%), with all responders experiencing a partial response (PR). Additionally, 52% of patients had stable disease, 12% experienced disease progression, and 4% were not evaluable. The disease control rate (DCR) was 84% (95% CI, 71.5%-91.6%).

Among patients evaluated retrospectively by blinded independent central review (BICR; n = 42), poziotinib elicited an ORR of 31% (95% CI, 19.1%-46%), with all responders experiencing a PR. Furthermore, 45% of patients had stable disease, 19% experienced disease progression, and 5% were not evaluable. The DCR was 76% (95% CI, 61.5%-86.5%).

“These data demonstrate that poziotinib is a clinically active and tolerable inhibitor of EGFR exon 20 insertion mutations with meaningful clinical activity in platinum-refractory patients, for whom limited therapeutic options are currently available, and that mechanisms of resistance to poziotinib in patients with EGFR exon 20–mutant NSCLC at least in part overlap with reported mechanisms of resistance to other EGFR inhibitors in patients with classical EGFR-mutant NSCLC,” lead study author Yasir Y. Elamin, MD, an assistant professor in the Department of Thoracic/Head and Neck Medical Oncology of the Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center, and colleagues, wrote.

Approximately 15% of all patients with NSCLC harbor EGFR mutations. Most of those cases feature classical EGFR exon 19 deletions and L858R mutations, where treatment with TKIs can produce meaningful ORRs. However, the approximately 10% of patients with NSCLC harboring EGFR exon 20 mutations are generally more resistant to EGFR TKIs.

In February 2022, the FDA accepted for review a new drug application for poziotinib in patients with previously treated locally advanced or metastatic NSCLC with HER2 exon 20 insertion mutations, based on results from cohort 2 of the phase 2 ZENITH20 trial (NCT03318939).2 In cohort 1 of that trial, which featured patients with EGFR exon 20–mutated NSCLC, poziotinib produced an ORR of 14.8% with a DCR of 68.7%.

The phase 2 study detailed here further explored the efficacy, safety, potential mechanisms of resistance, and molecular determinants of response for poziotinib. The trial enrolled patients who were at least 18 years of age with histologically or cytologically confirmed stage IV or recurrent solid tumors not amenable to curative intent therapy.3 Cohort 1 included patients with EGFR exon 20–mutated NSCLC.

Other key eligibility criteria included the need for adequate tissue for molecular profiling, measurable disease per RECIST v1.1 criteria, and an ECOG performance status of 0 or 1. Patients with stable brain metastases were permitted to enroll if they did not require treatment with anticonvulsants or escalating doses of steroids.

Key exclusion criteria included the presence of an EGFR T790M mutation or any other acquired EGFR exon 20 mutation (though patients with coexisting primary EGFR exon 20 and T790M mutations were eligible); prior or current treatment with an investigational agent or other systemic anticancer treatment within 2 weeks of first study dose; any concurrent chemotherapy, immunotherapy, biologic, or hormonal therapy for cancer treatment; or known or suspected brain metastases or spinal cord compression, unless the condition was asymptomatic, was treated with surgery/radiation, and has been stable without treatment at least 4 weeks prior to first study dose.

Once enrolled, patients were administered 16 mg of oral poziotinib once daily until objective disease progression. Patients were allowed to continue beyond progression if clinical benefit was observed. Patients who discontinued poziotinib for reasons other than disease progression continued to be assessed until progression occurred.

ORR per investigator and BICR assessments served as the primary end point of the trial. Secondary end points included DCR, progression-free survival (PFS), overall survival (OS), duration of response (DOR), and safety.

The median age of patients in cohort 1 was 62 years (range, 29-77), 60% were female, and 76% were White. Additionally, 28% had brain metastases at baseline, 68% never smoked, and 96% presented with adenocarcinoma. Ninety-four percent of patients had EGFR exon 20 insertion mutations, and 6% had exon 20 point mutations. Prior lines of therapy included 0 (6%), 1 (26%), 2 (34%), 3 (22%), and 4 or more (12%). Prior treatments included platinum-based chemotherapy (88%), a TKI (34%), and a PD-1/PD-L1 inhibitor (54%).

Additional investigator-assessed data showed that the median DOR was 8.6 months (95% CI, 3.7-19.3). Patients achieved a median PFS of 5.5 months (95% CI, 5.4-10.4), and the 6- and 12-month PFS rates were 43% (95% CI, 30%-60%) and 29% (95% CI, 18%-46%), respectively. The median OS was 19.2 months (95% CI, 11.8-24.1).

Patients who received prior platinum-based chemotherapy experienced an ORR of 34.1% (95% CI, 21.9%-48.9%) and a median PFS of 5.5 months (95% CI, 5.0-9.4). In patients with baseline brain metastases, the intracranial ORR and DCR were 14% and 86%, respectively.

Regarding the locations of EGFR exon 20 mutations, patients with insertions occurring in the near-loop region proximal to the αC helix achieved an ORR of 46% compared with 0% for patients with insertions in the distal far-loop region (P = .0015). Although the median PFS was not significantly different based on insertion location, the 6- and 12-month PFS rates were 47% (95% CI, 33%-67%) and 32% (95% CI, 19%-52%), respectively, for patients with near-loop insertions, compared with 30% (95% CI, 12%-76%) and 20% (95% CI, 6%-68%), respectively, for patients with far-loop insertions.

“The likelihood of response was highly dependent on the location of the exon 20 insertion, and that there was an inverse correlation between distance of the insertion from the αC helix and sensitivity to the drug both preclinically and in patients,” study authors wrote.

Additionally, study authors also revealed factors linked to resistance to poziotinib.

“Acquired resistance to poziotinib in preclinical models of EGFR exon 20 was associated with both EGFR-dependent mechanisms, including acquired T790M and C797S mutations, and EGFR-independent mechanisms, such as EMT,” they wrote. “Notably, T790M, but not C797S, mutations were detected in patients resistant to poziotinib treatment. In addition, signal bypass through MET amplifications and PI3K mutations was also observed in patients but not in preclinical models.”

The median duration of treatment with poziotinib was 5.8 months (interquartile range, 3.6-12.3). Of the 32 patients to experience disease progression, 32 were still alive at data cutoff, and 16 patients continued treatment with poziotinib following progression. The median duration of treatment after progression was 3.2 months (IQR, 2.5-5.6). Overall, 56% of patients had died at the time of data cutoff, and all deaths were considered related to NSCLC.

Regarding safety, the most common adverse effects (AEs) of any grade included diarrhea (92%), skin rash (90%), paronychia (68%), oral mucositis (68%), dry skin (60%), anorexia (40%), alopecia (38%), hypokalemia (34%), nausea (28%), vomiting (32%), fatigue (20%), weight loss (16%), and pruritus (14%). Grade 3 AEs included skin rash (34%), diarrhea (22%), paronychia (10%), hypokalemia (6%), nausea (6%), weight loss (4%), and oral mucositis (2%).

References

  1. Elamin YY, Robichaux JP, Carter BW, et al. Poziotinib for EGFR exon 20-mutant NSCLC: clinical efficacy, resistance mechanisms, and impact of insertion location on drug sensitivity. Cancer Cell. 2022;40(7):754-767.e6. doi:10.1016/j.ccell.2022.06.006
  2. Spectrum Pharmaceuticals announces acceptance of new drug application filing for poziotinib. News release. Spectrum Pharmaceuticals; February 11, 2022. Accessed July 13, 2022. https://bit.ly/3gGReox
  3. Poziotinib in EGFR exon 20 mutant advanced NSCLC. ClinicalTrials.gov. Updated June 27, 2022. Accessed July 13, 2022. https://clinicaltrials.gov/ct2/show/NCT03066206
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